American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Inhibition of eCIRP attenuates PANoptosis and renal fibrosis.
Zhang F, Jin H, Jacob A … +2 more , Brenner M, Wang P
Am J Physiol Renal Physiol · 2025 Sep · PMID 40857157 · Full text
Extracellular cold-inducible RNA-binding protein (eCIRP) was discovered as a potent damage-associated molecular pattern (DAMP). It has been shown that eCIRP is linked to various types of programmed cell death and acute i...
Extracellular cold-inducible RNA-binding protein (eCIRP) was discovered as a potent damage-associated molecular pattern (DAMP). It has been shown that eCIRP is linked to various types of programmed cell death and acute inflammation. However, the role of eCIRP in chronic inflammation and renal fibrosis has not been elucidated. Accumulating evidence indicates that renal tubular epithelial cells (RTECs) play a significant role in renal fibrosis. C23, a small molecular peptide inhibitor of eCIRP, has been implicated as a therapeutic agent in the context of acute inflammation and tissue injury. PANoptosis or synchronized cell death is observed as simultaneous triggering of apoptosis, pyroptosis, and necroptosis. However, its role in renal fibrosis is not known. We therefore hypothesize that eCIRP induced-chronic inflammation and injury in RTECs are mediated by PANoptosis and that inhibition of eCIRP by C23 decreases RTEC PANoptosis and attenuates renal injury and fibrosis in a mouse model of unilateral ureter obstruction (UUO) injury. By using primary RTECs, we demonstrated that eCIRP induces inflammatory cytokines, Z-DNA-binding protein-1, and other PANoptosome markers and markers of apoptosis, pyroptosis, and necroptosis. We then substantiated that C23 downregulated proinflammatory cytokines and inhibited PANoptosis in the RTECs. Using the UUO mouse model, we demonstrated renal cell PANoptosis and renal fibrosis 7 days after UUO. Importantly, treatment with C23 effectively inhibited PANoptosis and concurrently ameliorated renal fibrosis. Taken together, eCIRP induces inflammation and PANoptosis in RTECs, whereas C23 inhibits PANoptosis in these cells and attenuates renal fibrosis in UUO mice. Renal fibrosis is a common pathological manifestation of chronic kidney disease (CKD). Extracellular cold-inducible RNA-binding protein (eCIRP) was discovered as a potent damage-associated molecular pattern (DAMP). eCIRP is linked to various types of programmed cell death. PANoptosis or synchronized cell death is observed as simultaneous triggering of apoptosis, pyroptosis, and necroptosis. Inhibiting eCIRP by C23, a small molecular peptide inhibitor of eCIRP, attenuated PANoptosis and renal fibrosis in CKD.
Focal adhesion kinase inhibition induces membrane accumulation of aquaporin-2 in renal epithelial cells by actin depolymerization and endocytosis inhibition.
Tchakal-Mesbahi A, He J, Zhu S … +5 more , Huang M, Fukushima K, Bouley R, Brown D, Lu HAJ
Am J Physiol Renal Physiol · 2025 Oct · PMID 40857140 · Full text
Vasopressin (VP)-induced cellular trafficking of the water channel aquaporin-2 (AQP2) to maintain systemic water balance is regulated in large part by the actin cytoskeleton in collecting duct principal cells (PCs). Acti...
Vasopressin (VP)-induced cellular trafficking of the water channel aquaporin-2 (AQP2) to maintain systemic water balance is regulated in large part by the actin cytoskeleton in collecting duct principal cells (PCs). Actin depolymerization/polymerization is involved in both constitutive AQP2 recycling and the VP-stimulated pathway; in many cells, focal adhesion kinase (FAK) modulates the actin cytoskeleton by inhibiting small GTPases. To understand the contribution of FAK to this process, we examined its involvement in AQP2 trafficking. We first showed that FAK inhibition using the drug VS-4718 caused membrane accumulation of AQP2 in LLC-AQP2 epithelial cells in culture and PC in situ (kidney slices), by immunofluorescence staining and biotinylation. This was associated with significantly reduced endocytosis of AQP2 via the clathrin-mediated pathway, along with a reduction in RhoA activation and F-actin depolymerization. Importantly, AQP2 membrane accumulation induced by VS-4718 also occurred in cells expressing the dephosphorylation mutant of AQP2, S256A. Unlike VP, FAK inhibition did not increase cellular cAMP, nor AQP2 S256 phosphorylation. As expected, treatment with the FAK inhibitor VS-4718 suppressed FAK phosphorylation at Tyr397 in both cultured cells and kidney tissue. However, VP stimulation induced a redistribution of phospho-FAK (Tyr397) from basolateral toward the apical region of collecting duct principal cells in tissue slices, concomitant with AQP2 accumulation, but no overall change in the level of FAK phosphorylation was detectable after VP treatment. These data, therefore, identify FAK signaling as a distinct pathway that could provide a novel therapeutic avenue for regulating AQP2 trafficking in water balance disorders. Focal adhesion kinase (FAK) signaling plays a previously unrecognized role in regulating AQP2 trafficking by modulating the actin cytoskeleton and inhibiting the small GTPase RhoA in renal epithelial cells. Our findings demonstrate that FAK inhibition reduces AQP2 endocytosis via a cAMP- and serine 256 phosphorylation-independent mechanism, leading to its membrane accumulation. This study identifies FAK as a potential therapeutic target for water balance disorders by revealing its role in actin-mediated AQP2 regulation through RhoA inhibition.
Role of nuclear receptors, lipid metabolism, and mitochondrial function in the pathogenesis of diabetic kidney disease.
Hughes E, Wang XX, Sabol L … +6 more , Barton K, Hegde S, Myakala K, Krawczyk E, Rosenberg A, Levi M
Am J Physiol Renal Physiol · 2025 Oct · PMID 40828784 · Full text
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and remains a significant clinical challenge due to its complex pathogenesis. This review explores the intricate interplay of metabolic,...
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and remains a significant clinical challenge due to its complex pathogenesis. This review explores the intricate interplay of metabolic, inflammatory, and cellular mechanisms that drive DKD progression, with a particular focus on lipid metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell injury, and epigenetic modifications. Advances in histopathological and molecular studies have expanded our understanding of glomerular, tubular, and vascular abnormalities in DKD, highlighting the critical role of nuclear hormone receptors, transcription factors, and G protein-coupled receptors in regulating renal lipid accumulation, mitochondrial function, inflammation, oxidative stress, and fibrotic pathways. In addition, emerging evidence implicates novel cell death mechanisms, including ferroptosis, necroptosis, pyroptosis, and PANoptosis, in DKD pathology. Epigenetic modifications, including DNA methylation, histone modifications, and noncoding RNAs, further contribute to disease progression by regulating gene expression in response to metabolic stress. As current therapeutic strategies remain insufficient to prevent DKD progression, this review also discusses novel molecular targets and emerging therapeutic approaches aimed at mitigating lipid toxicity, enhancing mitochondrial function, and suppressing inflammation. By integrating insights from histopathology, molecular biology, and translational research, this review provides a comprehensive framework for developing future strategies to delay or prevent DKD progression.
The impact of chronic kidney disease on arteriovenous fistula remodeling: studies in a murine model of autosomal dominant polycystic kidney disease.
Laboyrie SL, Peters DJM, Bijkerk R … +5 more , de Winter EP, Duijs JMGJ, de Klerk JA, de Vries MR, Rotmans JI
Am J Physiol Renal Physiol · 2025 Oct · PMID 40824905 · Publisher ↗
The arteriovenous fistula (AVF) is the gold standard for hemodialysis vascular access, although inadequate vascular remodeling and intimal hyperplasia pose a major limitation. It is essential to study this in a clinicall...
The arteriovenous fistula (AVF) is the gold standard for hemodialysis vascular access, although inadequate vascular remodeling and intimal hyperplasia pose a major limitation. It is essential to study this in a clinically relevant model. We used an autosomal dominant polycystic kidney disease (ADPKD) model, the most common hereditary cause of chronic kidney disease (CKD), to study the effect of CKD on AVFs. Jugular-carotid AVFs were created in adult (ADPKD) mice and littermates. AVFs were harvested 7 days postsurgery for bulk mRNA sequencing or 3 wk postsurgery for histological analysis. We performed weekly AVF flow measurements using Doppler ultrasound and assessed kidney morphology and function by histology and blood urea analysis. Blood pressure was measured using a tail cuff, before and 6 days after AVF surgery. Longitudinal flow data was analyzed using mixed-effects model, histological data using the Mann-Whitney test. mice developed cystic kidneys and elevated blood urea levels (8.7 ± 2.8 mmol/L vs. 24.0 ± 3.8 mmol/L) and higher mean arterial blood pressure (92 vs. 113). AVF flow in mice was consistently higher post-AVF creation (1.9-fold difference, < 0.001), with a 50% reduction in intimal hyperplasia and 30% increase in luminal AVF volume. RNA sequencing showed altered regulation of extracellular matrix in the venous ADPKD AVF, with reduced collagen deposition in the venous outflow tract. The arterial AVF wall had disruption of the elastic laminae. mice are a suitable model to study AVF remodeling in a CKD setting, resulting in enhanced luminal volume and higher AVF flow when compared with normotensive mice with normal kidney function. This work explores the impact of chronic kidney disease (CKD) on arteriovenous fistula (AVF) remodeling using an autosomal dominant polycystic kidney disease (ADPKD) mouse model. Our findings reveal that ADPKD enhances AVF flow and luminal volume while reducing intimal hyperplasia, due to altered extracellular matrix deposition, offering new insights into the vascular AVF changes in a CKD setting. This study highlights the suitability of the ADPKD model for investigating AVF remodeling in a CKD context.
Impaired vascular function in patients with chronic kidney disease who have elevated symmetric dimethylarginine but not asymmetric dimethylarginine.
Grotle AK, Kaur J, Skow RJ … +6 more , Alhalimi TA, Young BE, Nandadeva D, Stephens BY, Mohan P, Fadel PJ
Am J Physiol Renal Physiol · 2025 Sep · PMID 40811822 · Full text
Chronic kidney disease (CKD) is associated with heightened cardiovascular disease (CVD) risk, partly due to impaired peripheral vascular function. Symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA)...
Chronic kidney disease (CKD) is associated with heightened cardiovascular disease (CVD) risk, partly due to impaired peripheral vascular function. Symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) are emerging biomarkers implicated in nitric oxide (NO) regulation and vascular health. Although ADMA is a well-established inhibitor of NO synthesis, recent evidence suggests that SDMA may also play a critical role in vascular health, especially in CKD before end-stage. Thus, in 23 stages 3 and 4 patients with CKD (66 ± 9 yr) and 32 age-matched controls (64 ± 8 yr), we compared serum SDMA and ADMA levels and examined their associations with vascular function, including flow-mediated dilation (FMD), peak blood velocity to reactive hyperemia, and carotid-femoral pulse wave velocity (cfPWV). SDMA was significantly elevated in patients with CKD (163 ± 37 vs. 100 ± 15 ng/mL, < 0.0001), while ADMA did not differ significantly between groups (111 ± 22 vs. 103 ± 12 ng/mL, = 0.083). Patients with CKD had lower FMD (3.66 ± 2.45 vs. 4.47 ± 2.45%, = 0.048) and peak blood velocity (47.43 ± 16.67 vs. 60.18 ± 16.88 cm/s, = 0.009), but higher cfPWV (8.82 ± 1.53 vs. 7.69 ± 1.35 m/s, = 0.004) than controls. Pooled analysis revealed that SDMA correlated inversely with eGFR ( = -0.86, < 0.0001), FMD ( = -0.28, = 0.039), and peak blood velocity ( = -0.40, = 0.001) but not cfPWV ( = 0.14, = 0.338). ADMA correlated inversely with peak blood velocity ( = -0.28, = 0.042) but not eGFR ( = -0.25, = 0.063), FMD ( = -0.06, = 0.664), or cfPWV ( = 0.21, = 0.146). Collectively, these findings suggest that SDMA, relative to ADMA, may be a stronger marker of vascular dysfunction in stages 3 and 4 CKD. However, the predictive value of SDMA for vascular function was modest, which may limit its overall potential as a biomarker for vascular function in CKD. The associations between symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) and measures of vascular function were investigated in patients with stage 3-4 chronic kidney disease (CKD). We found that SDMA exhibited stronger relationships with vascular function than ADMA. However, the strength of associations was modest, potentially limiting their role as standalone predictors of vascular dysfunction. Nonetheless, these data support emerging evidence of a differential impact of SDMA and ADMA in patients with CKD.
Exercise sensitizes the pressure diuresis response: shifting immune landscapes may underlie renal adaptations.
Jones SP, O'Leary N, Pena Calderin E … +7 more , Singhal R, Hellmann J, Damacena de Angelis C, Brittian KR, Welling PA, Nong Y, Sears SM
Am J Physiol Renal Physiol · 2025 Sep · PMID 40789206 · Full text
Physical activity and exercise confer health benefits through actions on several physiological systems; however, the mechanisms by which they impact renal health remain poorly understood. Studies show that exercise slows...
Physical activity and exercise confer health benefits through actions on several physiological systems; however, the mechanisms by which they impact renal health remain poorly understood. Studies show that exercise slows age-related decline in kidney function and protects against acute kidney injury (AKI). We hypothesize that exercise triggers adaptative responses, which preserve hemodynamic balance in the kidneys under stress. We evaluated running-induced adaptations in 10-14-wk-old C57BL/6J male and female mice subjected to voluntary running or in male mice subjected to forced treadmill running. We evaluated renal perfusion with contrast-enhanced ultrasound and assessed kidney function by measuring the ability to clear a volume load. In addition, we performed flow cytometry, cytokine array, histopathology, and bulk mRNA sequencing. We found that exercise significantly increased cortical microvascular blood volume ( = 0.0085), as indicated by increased plateau contrast signal intensity. In addition, exercised male, but not female, mice excreted significantly more urine in the first hour after a saline bolus ( = 0.0055). At the cellular level, we observed a significant increase in kidney resident macrophages (KRMs; CD45CD11bF4/80) after treadmill training in male mice. Finally, bulk mRNA sequencing suggested that treadmill training induced changes relating to water and sodium handling as well as angiogenesis and wound healing. These data suggest that exercise alters the immune landscape of the kidney, increases renal microvascular volume, and improves sensitivity of the pressure diuresis response. Future studies will test the hypothesis that macrophages cause the functional adaptations observed. The kidneys exhibit functional and cellular adaptations to exercise, such as increased renal cortex microvascular volume, as indicated by increased signal intensity of contrast-enhanced ultrasound. Exercise improves efficiency of pressure diuresis in male mice, reducing time needed to excrete an isotonic volume excess. At the cellular level, exercise expands kidney resident macrophage populations and alters transcriptional pathways relating to water and sodium handling, angiogenesis, and wound healing.
A multiscale vascular atlas of blood vessels supplying the urinary bladder of male and female mice.
Bowden LD, Daglas M, Osborne PB … +1 more , Keast JR
Am J Physiol Renal Physiol · 2025 Sep · PMID 40763078 · Full text
The vascular supply of the urinary bladder is embedded within a highly dynamic environment that includes alternating cycles of regional compression or stretching during bladder filling, sustained continence, and voiding....
The vascular supply of the urinary bladder is embedded within a highly dynamic environment that includes alternating cycles of regional compression or stretching during bladder filling, sustained continence, and voiding. These place unique demands on the vasculature to maintain tissue perfusion, fluid homeostasis, and immune surveillance. Understanding this vascular regulation is also highly relevant to defining mechanisms of organ reperfusion following pelvic surgery, pelvic venous insufficiency, and the impacts of diabetes and ischemia on urinary function. There is limited anatomical knowledge on the organization of this vascular network, so we aimed to determine if there are stereotypical features associated with the mouse urinary bladder. We applied advanced microscopy and anatomical visualization methods to samples of the entire bladder viewed as a whole mount, including intravital tomato lectin labeling of the arterial vasculature, multichannel immunofluorescence, tissue clearing, light sheet, and confocal microscopy. We developed a comprehensive multiscale three-dimensional anatomical map of the stereotypical arterial and venous networks associated with the mouse urinary bladder in both sexes, showing that the primary features of this network are established by the early postnatal period, before maturation of voiding and continence reflexes. These outcomes provide the foundation for probing mechanisms that underpin physiological and pathophysiological changes in the urinary bladder vascular network and a resource to guide more refined experimental perturbation, analysis, and interpretation of vascular function/dysfunction in mouse models. This new knowledge on the structure of the urinary bladder vascular network will also benefit tissue engineering efforts seeking to restore or replace this organ. The vasculature of the urinary bladder is embedded within a highly dynamic environment impacted by cycles of voiding and continence, placing unique demands on tissue perfusion and immune surveillance. This study has applied multiscale microscopy to reveal stereotypical vascular patterning in specific regions and tissues of the urinary bladder of male and female mice, providing a new understanding of organ circulatory support and a resource for studies on bladder function, pathophysiology, and organ engineering.
The nephronophthisis protein / is required for the DNA damage response in kidney tubular epithelial cells.
Ebert LK, Schloesser L, Frech LE … +6 more , Jain M, Dafinger C, Liebau MC, Benzing T, Schermer B, Slaats GG
Am J Physiol Renal Physiol · 2025 Sep · PMID 40713016 · Publisher ↗
Nephronophthisis (NPH) is an autosomal-recessive cystic kidney disease representing the most frequent genetic cause of end-stage kidney failure in children and adolescents. NPH is caused by genetic variants in >20 NPHP g...
Nephronophthisis (NPH) is an autosomal-recessive cystic kidney disease representing the most frequent genetic cause of end-stage kidney failure in children and adolescents. NPH is caused by genetic variants in >20 NPHP genes. Although nearly all NPHP genes encode ciliary proteins, classifying NPH as a renal ciliopathy, there is evidence for a pathogenic role of a compromised DNA damage response (DDR). Here, we present a novel -deficient mouse model with an early stop codon using CRISPR/Cas9-mediated genome editing (). Homozygous mice displayed dilated kidney tubules progressing to cystic kidney disease with significant fibrosis at a higher age. Interestingly, the kidneys of these animals exhibited an accumulation of DNA damage (DD) early on, even before any functional impairment of the kidneys became apparent. Interactome analysis for GLIS2 revealed an array of DDR-related proteins within the GLIS2 protein complex. Consistent with the in vivo data, the knockdown of in kidney epithelial cells led to increased DNA damage. Moreover, supporting the role of GLIS2 in the DDR, we demonstrate that a substantial proportion of GLIS2 is present within the chromatin fraction of cells, which is further increased upon UV-induced DD. Live-cell imaging revealed the rapid recruitment of green fluorescent protein (GFP)-tagged GLIS2 to sites of laser-induced DD, a response diminished in Glis2 and a variant of Glis2 resembling a known patient mutation. Overall, our data provide compelling evidence for the direct involvement of GLIS2 in the DDR, highlighting the loss of genome stability as an important factor contributing to the pathogenesis of renal ciliopathies. Nephronophthisis (NPH) is a pediatric cystic kidney disease and ciliopathy. We present a novel -deficient mouse model that shows early accumulation of DNA damage before detectable kidney dysfunction. The GLIS2 protein complex includes DNA damage response factors. GLIS2 localizes to chromatin and rapidly relocates to sites of DNA damage. These findings position GLIS2 as a direct player in genome stability, highlighting impaired DDR as a key contributor to NPH pathogenesis.
Targeting the endocannabinoid system to suppress mTORC1 hyperactivation in TSC-associated kidney disease.
Abergel E, Pri-Chen H, Wallach-Dayan S … +4 more , Hinden L, Tam J, Volovelsky O, Nechama M
Am J Physiol Renal Physiol · 2025 Sep · PMID 40707038 · Publisher ↗
Tuberous sclerosis complex (TSC) promotes renal cyst formation and chronic kidney disease through mechanistic target of rapamycin complex 1 (mTORC1) dysregulation, yet effective treatments remain limited. Using mouse mod...
Tuberous sclerosis complex (TSC) promotes renal cyst formation and chronic kidney disease through mechanistic target of rapamycin complex 1 (mTORC1) dysregulation, yet effective treatments remain limited. Using mouse models with deletion in nephron progenitor cells and CRISPR-edited human kidney cells, we assessed the role of the endocannabinoid system in TSC-associated kidney disease. deletion led to significant alterations in endocannabinoid levels and the expression of metabolizing enzymes. These molecular changes were accompanied by receptor dysregulation, characterized by CB1R upregulation and CB2R downregulation in cyst-lining epithelial cells. A similar receptor imbalance was observed in -deficient human kidney cells, suggesting a conserved pathogenic mechanism. Treatment with the peripheral CB1R antagonist JD5037 significantly reduced mTORC1 activity and c-Myc expression in cultured cells and ex vivo kidney organ cultures. These findings identified CB1R as a potential therapeutic target, linking endocannabinoid dysregulation to TSC kidney pathology. This study reveals for the first time that TSC-associated kidney disease involves significant dysregulation of the endocannabinoid system in both murine models and human kidneys, characterized by altered endocannabinoid levels, enzyme expression changes, CB1R upregulation, and CB2R downregulation in cyst-lining epithelial cells. Treatment with the peripheral CB1R antagonist effectively suppressed mTORC1 hyperactivation and c-Myc expression, identifying CB1R as a novel therapeutic target for TSC-associated renal pathology.
Macula densa nitric oxide synthase 1β restoration by kidney alkalization enhances renal graft outcomes.
Parris CL, Liu C, Rani A … +5 more , Tran MH, Li M, Esquivel C, Oropeza A, Wang L
Am J Physiol Renal Physiol · 2025 Sep · PMID 40691045 · Full text
Ischemia-reperfusion injury (IRI) remains a critical challenge to the survival of kidney transplantation (KTX) graft, with no effective prevention or treatment strategies currently available. Neuronal nitric oxide syntha...
Ischemia-reperfusion injury (IRI) remains a critical challenge to the survival of kidney transplantation (KTX) graft, with no effective prevention or treatment strategies currently available. Neuronal nitric oxide synthase 1β (NOS1β), the predominant splice variant of NOS1 and the main source of NO in the macula densa (MD), mediates tubuloglomerular feedback and regulates glomerular filtration rates. NOS1β activity in the MD is influenced by renal pH; however, the role of pH-dependent regulation of NOS1β in mitigating IRI and protecting transplanted kidney graft function remains unclear. To explore this, C57BL/6J mice were given oral sodium bicarbonate (NaHCO) or NaCl for 2 wk before KTX. Blood and urine pH, NOS1β expression, NO levels, and transplant outcomes were evaluated. MD-specific NOS1 knockout (MD-NOS1KO) mice were used to assess the direct role of NOS1β. NOS1β expression decreased by approximately 60% 3 days after KTX. MD-NOS1β deletion exacerbated graft injury. NOS1β activities showed a strong tubular pH dependence, with maximal activity near pH 8.0. Bicarbonate treatment increased NOS1β expression in the MD by 65% and significantly improved graft outcomes, lowering plasma creatinine by ∼30% relative to NaCl-treated group. These protective effects were absent in MD-NOS1KO mice. Proteomic analysis revealed 718 differentially expressed proteins, with several showing enrichment in NO signaling, tissue repair, and inflammatory response pathways. In summary, MD-NOS1β downregulation after transplantation contributes to graft injury. Raising renal pH with bicarbonate enhances NOS1β activity and protects graft function, suggesting a potential therapeutic strategy to reduce IRI in kidney transplants. This study reveals that raising renal tubular pH with oral bicarbonate enhances macula densa-specific NOS1β activity, protecting against ischemia-reperfusion injury in kidney transplants. These benefits are lost in macula densa NOS1β knockout mice, confirming its key role in graft protection. The findings suggest that modulating renal pH is a promising, noninvasive strategy to improve transplant outcomes by targeting macula densa-NOS1β.
Pathophysiological response in trauma-related acute kidney injury after blunt thoracic trauma and hemorrhagic shock in male mice.
Halbgebauer R, Schult L, Borgel O … +13 more , Maes A, Weißhaupt F, Rastner C, Ast A, Lupu L, Palmer A, Wachter U, Schmidt SA, Boor P, Rösler R, Wiese S, Kerckhofs G, Huber-Lang MS
Am J Physiol Renal Physiol · 2025 Aug · PMID 40668650 · Publisher ↗
Trauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. To study the pathophysiology of TRAKI, we estab...
Trauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. To study the pathophysiology of TRAKI, we established a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage [trauma and hemorrhagic shock (THS)] that induces mild transient TRAKI. The mice displayed early and transiently increased plasma creatinine, urea, and neutrophil gelatinase-associated lipocalin and urine albumin, resolving 5 days after TRAKI induction. Morphological changes were only observed at the microscopic level, where proximal tubular cell damage and brush border loss were evident. We furthermore found kidney stress responses, for example, with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes following trauma. Three-dimensional x-ray-based whole organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood filling, particularly during the first day after THS, which was partly resolved by . Our novel murine TRAKI model revealed previously unknown aspects of the complex temporal pathophysiologic response of the kidney along the nephron following trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches. This study introduces a murine model of trauma-related acute kidney injury (TRAKI) via combined blunt thoracic trauma and hemorrhage, revealing transient kidney dysfunction despite normal morphology. Early damage to proximal tubular cells, inflammatory responses, and induction of stress markers like heme oxygenase-1 were observed. Proteomic analyses uncovered distinct intrarenal changes, whereas three-dimensional microcomputed tomography showed capillary blood supply impairment, resolving by . These findings shed light on TRAKI's pathophysiology and may inform future therapeutic strategies.
Valosin-containing protein in ciliary morphology: a novel target in ADPKD.
Pioppini C, Bhardwaj R, Schönauer R … +6 more , Halbritter J, Hassan F, Eckardt KU, Fedeles SV, Yilmaz DE, Krappitz M
Am J Physiol Renal Physiol · 2025 Aug · PMID 40662578 · Publisher ↗
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder leading to kidney cyst formation and loss of kidney function. The major causative genes and encode for the ciliary proteins polycystin-1 (PC...
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder leading to kidney cyst formation and loss of kidney function. The major causative genes and encode for the ciliary proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are involved in ciliary functions. Within -defective cells, the accumulation of misfolded PC1 proteins triggers the unfolded protein response (UPR). Among the pathways activated, the ER-associated degradation (ERAD), mediated by proteins such as valosin-containing protein (VCP), aims to alleviate the unfolded or misfolded protein burden. Our study investigates the genetic relationship between VCP and PC1-dependent cystogenesis. We found that the pharmacological inhibition of VCP ameliorates the cystic phenotype in -knockout mice. This effect is associated with increased ER stress-dependent apoptosis in PC1-deficient cells. In addition, we discovered that VCP is localized in the primary cilia and its inhibition affects cilia assembly and reduces the cilia length. Our findings identify VCP as a novel ciliary protein and a potential therapeutic target for ADPKD. We confirmed that VCP inhibition reduces cyst burden in vivo and selectively induces apoptosis in -deficient cells in vitro via UPR-activation. In addition, VCP regulates cilia assembly and morphology, binding together proteostasis and ciliary dynamics. The results of this study support VCP as a modulator of cystogenesis and offer a novel therapeutical strategy for ADPKD. By selectively promoting apoptosis in PC1-deficient cells and modulating their ciliary functions, VCP inhibition may offer a novel approach to treat ADPKD.
Renal ischemia-reperfusion injury triggers proximal tubular apoptosis and NHE3 dysfunction via p38MAPK/ezrin signaling pathway.
Costa-Pessoa JM, de Ponte MC, Braz HM … +3 more , Cruz MC, Lopes-Gonçalves G, Oliveira-Souza M
Am J Physiol Renal Physiol · 2025 Aug · PMID 40610014 · Publisher ↗
Acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) contributes to a high rate of morbidity and mortality in many clinical settings. We hypothesized that I/R-induced proximal tubule (PT) injury is associated...
Acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) contributes to a high rate of morbidity and mortality in many clinical settings. We hypothesized that I/R-induced proximal tubule (PT) injury is associated with inflammation and apoptosis and that PT cell injury may impair Na/H exchanger isoform 3 (NHE3) activity. This study aimed to investigate the relationship between PT injury and NHE3 activity, analyzing the contribution of the p38MAPK/ezrin signaling pathway. To this end, we used in vivo and in vitro models of I/R. For the in vivo approach, 8-wk-old C57BL/6J mice were subjected to bilateral kidney I/R and compared with the sham-treated group. In vitro, TKPTS cells (mouse proximal tubular cell line) were subjected to I/R by treatment with antimycin A (5 µM) and/or SB203580 (1 µM; p38MAPK inhibitor) or NSC305787 (3.2 µM; ezrin phosphorylation inhibitor) and compared with respective controls. Renal I/R in mice resulted in PT injury, severe inflammation, increased p38MAPK activation, reduced phospho (p-)ezrin immunostaining, and decreased colocalization of NHE3 with both villin and p-ezrin. Similarly, in vitro I/R caused cell apoptosis, increased p38MAPK activation, induced translocation of ezrin from the membrane to the cytosol, and reduced NHE3 activity. Thus, these findings suggest that in ischemic AKI tubulointerstitial injury is driven by inflammation and apoptosis, mediated through p38MAPK activation and altered ezrin function, ultimately impairing NHE3 activity and exacerbating cell injury. This study demonstrated that renal ischemia-reperfusion (I/R) induces severe damage to the proximal tubular epithelium, mainly by exacerbating inflammatory and apoptotic responses. These responses are mediated by activated p38MAPK, which alters ezrin function and impairs NHE3 activity, exacerbating cell injury.
Inhibition of methylthioadenosine phosphorylase protects from experimental acute kidney injury.
Saliba A, Chen Y, Nelson JW … +8 more , Vetcha A, Wang WW, Kang L, Ragi N, Maity S, Rabb H, Reeves WB, Sharma K
Am J Physiol Renal Physiol · 2025 Aug · PMID 40602784 · Full text
Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfus...
Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfusion and cisplatin-induced acute kidney injury (AKI). MTAP inhibition was confirmed by the accumulation of methylthioadenosine. Treated mice showed reduced renal injury and decreased tubular damage. Transcriptomic analysis revealed protection from inflammatory and stress pathways while maintaining oxidative phosphorylation, fatty acid metabolism, and epithelial integrity-related genes. Analysis of human single-cell RNA sequencing data from the Kidney Precision Medicine Project indicated that MTAP is highly expressed in kidney injury marker-positive adaptive proximal tubule cells, which display both reparative and maladaptive features during AKI. These findings highlight MTAP as a potential therapeutic target for modulating injury responses in AKI. We show that prophylactic MTAP inhibition protects against experimental AKI in mice. Transcriptomic data indicate that MTAP inhibition suppresses epithelial stress and maladaptive repair-related gene programs. Single-cell analysis of human AKI biopsies supports a role for MTAP in injured proximal tubule subpopulations, identifying it as a potential therapeutic target in AKI.
Kidney organoids demonstrate that PTH1R drives a cystogenic cAMP-pPKA-pCREB axis in developmental polycystic kidney disease.
Afrin H, Robichaud JH, Qamar U … +2 more , Harris PC, Gupta N
Am J Physiol Renal Physiol · 2025 Aug · PMID 40602764 · Full text
Human pluripotent stem cell-derived kidney organoids have demonstrated utility in modeling kidney development and genetic disease. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited developmental cysti...
Human pluripotent stem cell-derived kidney organoids have demonstrated utility in modeling kidney development and genetic disease. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited developmental cystic kidney disease of high morbidity and mortality that lacks directed therapy. To overcome the limitations of animal models and stimulate drug discovery, ARPKD organoids have previously been subject to well-described cystogenic mechanisms for use in therapeutic screens. Although these studies have validated genotype-phenotype correlations and cystogenic response of ARPKD organoids as similar to existing in vitro models, novel cystogenic mechanisms that expand potential therapeutic targets have yet to be uncovered. Here we use a combination of human induced pluripotent stem cell-derived ARPKD and isogenic wild-type organoids, native kidney and organoid single-cell RNA sequencing, decedent human ARPKD tissue, and targeted mechanistic studies to describe PTH1R as a stimulatory G-protein-coupled receptor, which instigates a cystogenic signaling cascade in developmental cystic kidney disease. Our findings demonstrate the utility of kidney organoids as an in vitro model for pathomechanisms of rare diseases, which lack faithful animal models. Stem cell-derived kidney organoids enable human genetic disease modeling to identify the parathyroid hormone 1 receptor as a potential new therapeutic target for developmental polycystic kidney disease.
Mechanisms of anti-VEGF therapy-induced kidney injury: current insights and future perspectives in combination with immune checkpoint inhibitors.
Uyl TJJ, Ngo A, Pratt D … +5 more , Cortez I, Mathijssen RHJ, Versmissen J, Danser AHJ, Mirabito Colafella KM
Am J Physiol Renal Physiol · 2025 Aug · PMID 40602762 · Publisher ↗
The formation of new blood vessels is crucial for tumor and metastatic progression. Consequently, targeted therapies directed toward the vascular endothelial growth factor (VEGF) pathway have significantly improved treat...
The formation of new blood vessels is crucial for tumor and metastatic progression. Consequently, targeted therapies directed toward the vascular endothelial growth factor (VEGF) pathway have significantly improved treatment outcomes in several malignancies. These treatment modalities are frequently used in current oncologic practice, as monotherapy or in combination with other anticancer regimens such as immune checkpoint inhibitors (ICIs), to enhance the anticancer effects. Despite their proven efficacy, anti-VEGF therapies are also known to cause substantial kidney toxicity. Common kidney side effects include hypertension, proteinuria, kidney dysfunction, thrombotic microangiopathy, and in some cases, kidney failure. These adverse effects pose significant challenges in clinical practice, as kidney damage can lead to lower dosing of anticancer treatment and compromise quality of life. The mechanisms underlying kidney toxicity associated with anti-VEGF therapies, including in combination with ICIs, are poorly understood. A deeper understanding of these mechanisms is essential for mitigating kidney damage and preserving kidney function during treatment. This review aims to explore the role of VEGF in kidney physiology, the incidence of kidney toxicities associated with anti-VEGF therapies, and the potential mechanisms driving these toxicities, with particular emphasis on the endothelin, nitric oxide, and prostanoid pathways. In addition, the review will address the kidney effects observed when anti-VEGF therapies are combined with ICIs, as both treatment modalities are independently associated with kidney-related adverse effects, along with the underlying mechanisms involved.
Race and sex differences in pressor response to laboratory stressors in patients with chronic kidney disease.
Zanuzzi MG, Jeong J, Newton K … +2 more , Wang W, Park J
Am J Physiol Renal Physiol · 2025 Aug · PMID 40549567 · Full text
Black individuals, especially Black females, have higher prevalence of chronic kidney disease (CKD) and greater risk of CKD-related cardiovascular (CV) mortality compared with other racial groups. Patients with CKD have...
Black individuals, especially Black females, have higher prevalence of chronic kidney disease (CKD) and greater risk of CKD-related cardiovascular (CV) mortality compared with other racial groups. Patients with CKD have higher CV reactivity compared with those without CKD that contributes to increased CV risk in this patient population. However, race and sex differences in hemodynamic reactivity within CKD have not previously been explored. Given the known race and sex differences in the risk of CKD-related CV disease, we tested the hypothesis that Black individuals, especially Black females, with CKD will have greater CV reactivity to stress. Forty-three Black participants (32 males) and 20 White participants (12 males) with CKD stages III and IV were enrolled. Blood pressure (BP) and heart rate (HR) reactivity were evaluated during three laboratory stressors: mental arithmetic test (MAT), static handgrip exercise (SHG30%), and cold pressor test (CPT). Black participants had greater BP reactivity during MAT and greater HR reactivity during SHG30%, but no difference in CV reactivity during CPT compared with White participants. There were no sex differences in hemodynamic responses across all tests. Black females had greater BP reactivity during MAT and greater HR reactivity during SHG30% compared with White females. Black females had the highest CV responses across all tests. Black individuals, especially Black females, with CKD had greater CV reactivity during stressful stimuli compared with White individuals with CKD. These results highlight demographic influences on CV reactivity that may contribute to differences in CV outcomes in people with CKD. Among patients with chronic kidney disease, Black individuals-particularly Black females-exhibited heightened cardiovascular responses to different laboratory stressors compared with White individuals. The magnitude and pattern of cardiovascular reactivity varied by race and sex, with differential responses observed depending on the type of stressor applied. Elevated cardiovascular reactivity in Black individuals, especially Black females, may represent a mechanistic link contributing to their disproportionate burden of CKD-related cardiovascular disease.
Adverse functions of neutrophils are regulated by neutrophilic angiotensin-converting enzyme in immune complex-mediated crescentic glomerulonephritis.
Saito S, Kumakura S, Khan Z … +4 more , Bernstein EA, Karumanchi SA, Bernstein KE, Yamashita M
Am J Physiol Renal Physiol · 2025 Jul · PMID 40526025 · Publisher ↗
Neutrophils play a pathogenic role in immune complex (IC)-mediated crescentic glomerulonephritis (GN). Angiotensin-converting enzyme (ACE) plays a crucial role in regulating blood pressure and inflammation via angiotensi...
Neutrophils play a pathogenic role in immune complex (IC)-mediated crescentic glomerulonephritis (GN). Angiotensin-converting enzyme (ACE) plays a crucial role in regulating blood pressure and inflammation via angiotensin II. We recently reported that ACE-overexpressing neutrophils have the renoprotective role in IC-mediated crescentic GN by the complement C3b-complement receptor1/2 axis. Here, we further investigate the precise mechanism of the adverse, pathogenic, and renoprotective functions of neutrophils in GN. Nephrotoxic serum nephritis (NTN) was induced in the mice with four different conditions and analyzed: ) neutrophil depletion in wild-type (WT) and NeuACE mice that overexpress ACE specifically in neutrophils; ) adoptive transfer of ACE-overexpressing neutrophils into WT mice; ) analysis of ACE's catalytic C and N domains using each domain-knockout (Tg-CKO and Tg-NKO) and WT-ACE transgenic (Tg-ACE) mice; and ) comparison between C3KO and C3KO-NeuACE mice that overexpress ACE in neutrophils but lack of complement C3. The results were as follows: ) WT mice without neutrophils showed ameliorated glomerular injury, whereas neutrophil-depleted NeuACE mice lost the renoprotective effect; ) WT mice with ACE-overexpressing neutrophils exhibited less severe glomerular injury; ) Tg-CKO or Tg-NKO mice showed a partial loss of the renoprotective effects compared with Tg-ACE mice, suggesting both C and N domains are needed for full renoprotection; and ) C3KO-NeuACE mice lost the renoprotective effects. Complement C3 is essential for the renoprotection of overexpressed neutrophilic ACE in NeuACE mice. The present study demonstrated that canonical pathogenic effects of neutrophils were overcome by the noncanonical renoprotection by neutrophils through both C and N domains of ACE and complement C3. We recently reported that NeuACE mice that overexpress angiotensin-converting enzyme (ACE), specifically in neutrophils, alleviate glomerular injury in immune complex-mediated crescentic glomerulonephritis by the complement C3b-complement receptor 1/2 axis. Here, we showed that catalytically active C and N domains of ACE were needed for full renoprotection, and complement C3 was essential for the renoprotective role of overexpressed neutrophilic ACE. Furthermore, we highlighted the neutrophils' canonical pathogenic and noncanonical renoprotective functions via neutrophilic ACE through complement C3 in glomerulonephritis.
Pulsed ultrasound targeted to the spleen mitigates against kidney injury and promotes kidney repair.
Goggins E, Xie Y, Huang Y … +5 more , Brantley C, Yao J, Cechova S, Hossack JA, Okusa MD
Am J Physiol Renal Physiol · 2025 Aug · PMID 40506227 · Full text
Acute kidney injury (AKI) is a devastating condition with major complications including death and, in some cases, progression to chronic kidney disease (CKD). We have previously shown that pulsed ultrasound (pUS) can red...
Acute kidney injury (AKI) is a devastating condition with major complications including death and, in some cases, progression to chronic kidney disease (CKD). We have previously shown that pulsed ultrasound (pUS) can reduce kidney ischemia-reperfusion injury (IRI) by activating the cholinergic anti-inflammatory pathway. The efficacy of a spleen-targeted pUS regimen in AKI of other etiologies and its long-term impact are unclear. Using a new spleen-targeted US approach, pUS was delivered to male mice 24 h before folic acid (FA), lipopolysaccharide, or bilateral kidney IRI. Mice were monitored and assessed for markers of inflammation, renal function, and kidney fibrosis. When compared with sham, mice that received spleen-targeted pUS had reduced plasma TNFα and blood urea nitrogen (BUN) after sepsis-associated AKI, reduced plasma creatinine, and BUN after kidney IRI and reduced plasma creatinine, BUN, and kidney fibrosis after FA administration. pUS-treated mice displayed reduced myeloid cell infiltration to the kidneys after FA and IRI. In sham-treated mice, markers associated with ongoing maladaptive repair including , , and were increased on after FA in comparison with pUS-treated mice. These data demonstrate that pulsed ultrasound of the spleen is a novel, safe, and effective therapy for the prevention of AKI of multiple etiologies and the subsequent development of CKD. Findings from this study are critical for advancing human translation of ultrasound as a preventative measure for AKI and CKD. We developed a safe and effective pulsed ultrasound (pUS) protocol targeting the mouse spleen to block inflammation and reduce AKI of multiple etiologies. By using a model of the AKI to CKD transition, we demonstrated the long-term benefits of pUS. The findings of these studies will be used to advance the human translation of spleen-targeted US as a preventative measure for AKI and CKD.
Kidney organoid models of polycystic kidney disease: challenges and future directions.
Afrin H, Qamar U, Robichaud JH … +3 more , Ellabbad M, Harris PC, Gupta N
Am J Physiol Renal Physiol · 2025 Jul · PMID 40499561 · Full text
Kidney organoids are an increasingly established model of polycystic kidney disease (PKD). Derived from human pluripotent stem cells (hPSCs), organoids may be generated from induced pluripotent stem cells (iPSCs) of pati...
Kidney organoids are an increasingly established model of polycystic kidney disease (PKD). Derived from human pluripotent stem cells (hPSCs), organoids may be generated from induced pluripotent stem cells (iPSCs) of patients that bear naturally occurring mutations or from CRISPR mutant hPSCs by virtue of their genetic tractability. PKD is the leading inheritable cause of kidney failure (KF), accounting for ∼5%-10% of the kidney transplant and dialysis needs worldwide. PKD is a disorder of considerable genetic heterogeneity, composed of typical adult-onset autosomal dominant (ADPKD) and fetal-onset autosomal recessive (ARPKD) forms, which share pathomechanisms. Despite advances in our understanding of the genetic and molecular underpinnings of PKD, the limited clinical treatment options have raised concerns regarding the faithfulness of preclinical models. Kidney organoids have emerged as a promising platform to study PKD by mimicking human-specific responses, enabling personalized medicine, and supporting high-throughput screens. Yet, valid criticisms have related to the relative immaturity of kidney organoids for modeling adult-onset forms of PKD, the faithfulness of organoids in modeling the cystic distribution of afflicted patients, and their batch-to-batch variability limiting experimental reproducibility. Here, we summarize a decade of kidney organoid models of PKD, emphasizing their role in advancing translational and therapeutic applications while addressing their limitations and future potential.
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