American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Iron metabolism and ferroptosis: druggable targets to delay the progression of lupus nephritis.
Al-Hraki L, Morel L, Scindia Y
Am J Physiol Renal Physiol · 2026 Jan · PMID 41259109 · Full text
Lupus nephritis (LN) is the renal manifestation of the autoimmune disease systemic lupus erythematosus (SLE). LN is characterized by a dysregulated immune system, the presence of autoantibodies, and renal immune complex...
Lupus nephritis (LN) is the renal manifestation of the autoimmune disease systemic lupus erythematosus (SLE). LN is characterized by a dysregulated immune system, the presence of autoantibodies, and renal immune complex deposits, which collectively injure the kidney. However, novel nonimmune pathogenic mechanisms of human LN are continuously uncovered, presenting new challenges as well as opportunities for intervention. Iron accumulation and ferroptosis in the glomerular structure and renal tubules are relatively newly identified pathological features in LN. Ferroptosis is an iron-dependent nonapoptotic form of regulated cell death. Unlike generic oxidative stress mechanisms, ferroptosis occurs when the cellular antioxidative mechanism cannot suppress the oxidation of the cell membrane eventually leading to cell membrane rupture. Since iron absorption and recycling occur in the renal tubules, the renal tissue is particularly susceptible to ferroptosis. Ferroptosis inhibitors that reduce toxic phospholipid hydroperoxides to their corresponding nontoxic alcohols, or trap radicals in phospholipid bilayers, have improved disease outcomes in murine models of SLE/LN. In this review, we discuss mechanisms by which iron accumulation and ferroptosis perpetuate pathology in LN. These studies suggest that ferroptosis is very likely integral to parenchymal cell dysfunction in LN and a novel therapeutic target. The goal of this review is to introduce the fundamentals of iron biology and ferroptosis to clinicians and basic scientists and spur research to identify intracellular proferroptotic enzymes and their protein conjugates as potential targets to improve LN.
Macrophages and TGFB signaling regulate fibrosis in the -infected mouse prostate.
Scharpf BR, Sandhu J, Ruetten H … +15 more , Park H, Manuel R, Fox O, Turco AE, Nair SS, Heye E, Ambrogi M, Chandrashekar S, Pidikiti A, Rundquist A, Steers NJ, Arendt L, Suresh M, Strand DW, Vezina CM
Am J Physiol Renal Physiol · 2026 Jan · PMID 41259106 · Full text
Prostate inflammation and fibrosis are linked to lower urinary tract symptoms (LUTS) in men. Uropathogenic () infection of the mouse prostate triggers a cascade of immune responses that drive inflammation and fibrosis....
Prostate inflammation and fibrosis are linked to lower urinary tract symptoms (LUTS) in men. Uropathogenic () infection of the mouse prostate triggers a cascade of immune responses that drive inflammation and fibrosis. A recent study found that lysosome 2-positive (LYZ2+) myeloid cells (fibrocytes) are recruited in a C-C motif chemokine receptor 2 ()-dependent manner to the -infected prostate, where they produce collagen. This study aims to identify factors that drive collagen synthesis in LYZ2+ myeloid cells during infection. We show that lymphocyte antigen 6 family member (Ly6C) monocytes and their maturation products, Ly6C macrophages, infiltrate the infected prostate in a dependent manner, that monocytes in the infected prostate produce RNA, and that infection activates TGFB signaling and collagen synthesis in LYZ2+ cells. Blockade of macrophage colony-stimulating factor (M-CSF), a factor required for monocyte differentiation into macrophages, reduces macrophage density, TGFB signaling in LYZ2+ cells, and collagen density in the -infected prostate. These findings highlight a critical role of macrophages in activating collagen synthesis in fibrocytes to drive a fibrotic response to infection in the mouse prostate. Prostatic/urethral fibrosis is an emerging cause of urinary voiding dysfunction in aging men and has been linked to prostate inflammation, but cellular mediators and mechanisms of this process are incompletely understood. We provide evidence that Ly6C monocytes and LYZ2+ myeloid cells are recruited to the infected mouse prostate. Macrophages in the infected prostate synthesize TGFB1 and stimulate collagen synthesis in LYZ2+ cells.
Ad libitum drinking does not mitigate acute kidney injury risk nor elevations in markers of oxidative stress and inflammation during simulated occupational heat stress.
Tourula E, Hite MJ, Heikkinen ME … +6 more , Hess HW, Amorim FT, Mickleborough TD, Johnson BD, Hostler D, Schlader ZJ
Am J Physiol Renal Physiol · 2026 Jan · PMID 41236910 · Full text
This study tested the hypothesis that ad libitum fluid intake during a 2-h occupational heat stress simulation attenuates increases in renal oxidative stress, inflammation, and acute kidney injury (AKI) risk compared wit...
This study tested the hypothesis that ad libitum fluid intake during a 2-h occupational heat stress simulation attenuates increases in renal oxidative stress, inflammation, and acute kidney injury (AKI) risk compared with fluid restriction. Thirteen healthy adults (5 women) completed two 2-h occupational heat stress simulations consisting of eight circuits of treadmill walking and rowing exercise in a wet bulb globe temperature of 33.1 ± 0.2°C. In the drinking trial (Drink), participants were provided 237 mL of a noncaloric sport drink every 15 min and drank ad libitum. In the fluid restriction trial (No Drink), no fluid was provided. Urine and blood samples were analyzed for markers of oxidative stress (thioredoxin-1, TRX-1), inflammation (monocyte chemotactic protein-1, MCP-1), and AKI risk ([IGFBP7·TIMP-2]). During Drink, ad libitum fluid intake was 1,394 ± 316 mL, and reductions in body weight were greater in No Drink (1.3 ± 0.8% vs. 2.8 ± 0.9%, < 0.001). Peak core temperature was not different between Drink (38.5 ± 0.4°C) and No Drink [38.6 ± 0.4°C, mean difference (upper, lower CI): 0.1 (0.4, -0.1)°C; = 0.346]. Urine, but not serum TRX-1 ( = 0.254), was elevated at postrecovery and recovery ( < 0.001) but not different between trials ( = 0.743). Serum and urine MCP-1 were elevated at postrecovery and recovery ( < 0.001) but not different between trials ( ≥ 0.407). Urine [IGFBP7·TIMP-2] was elevated at postrecovery and recovery ( < 0.001) but not different between trials ( ≥ 0.096). Ad libitum fluid intake during a 2-h occupational heat stress simulation does not modify biomarkers of systemic and renal oxidative stress and inflammation, nor AKI risk, compared with when fluid is restricted. Ad libitum fluid intake, consistent with occupational hydration recommendations, does not attenuate renal oxidative stress, inflammation, or acute kidney injury risk during simulated heat stress. These findings challenge the assumption that current hydration recommendations are protective, suggesting that additional strategies are needed to mitigate heat-induced kidney injury in occupational settings.
New insight into plasma and organelle membrane repair to guard against cell death in tubular epithelium after acute kidney injury.
Wang SM, Li N, Qian WW … +6 more , Liu Q, Xu CH, Tang TT, Liu BC, Zhang T, Lv LL
Am J Physiol Renal Physiol · 2026 Jan · PMID 41236905 · Publisher ↗
Plasma membrane repair is crucial for resealing membrane disruptions from physiological and pathological stimuli to preserve cell integrity and homeostasis. Tubular epithelial cells (TECs) die of unrepaired membrane inju...
Plasma membrane repair is crucial for resealing membrane disruptions from physiological and pathological stimuli to preserve cell integrity and homeostasis. Tubular epithelial cells (TECs) die of unrepaired membrane injury induced by biochemical and immune factors, leading to the onset and progression of acute kidney injury (AKI). Indeed, mammalian cells are equipped with repair pathways and molecular machinery to safeguard cell viability. Depending on the severity and nature of plasma membrane injury, membrane disruptions can be resealed by vesicle-dependent and independent approaches. Besides, the process of membrane resealing is also important for the repair of damaged organelle membranes. Herein, different formats of plasma membrane damage were discussed, highlighting the membrane disruption induced by pore-forming proteins (PFPs), including MAC, perforin, and membrane-damaging proteins in regulated cell death (RCD). Moreover, the mechanisms of plasma and organelle membrane repair to guard against the death of TECs in AKI were discussed, with the aim of proposing novel strategies for AKI therapy.
Spleen tyrosine kinase signaling in myeloid cells promotes macrophage infiltration, glomerulosclerosis, and interstitial fibrosis in diabetic kidney disease.
Chia XX, Ozols E, Nikolic-Paterson DJ … +1 more , Tesch GH
Am J Physiol Renal Physiol · 2025 Dec · PMID 41223081 · Publisher ↗
Macrophages have been implicated in causing renal injury in diabetic kidney disease (DKD). Spleen tyrosine kinase (SYK) plays an important role in signaling via a number of cell surface receptors that promote recruitment...
Macrophages have been implicated in causing renal injury in diabetic kidney disease (DKD). Spleen tyrosine kinase (SYK) plays an important role in signaling via a number of cell surface receptors that promote recruitment and activation of myeloid cells, but whether SYK signaling is involved in DKD is unknown. Therefore, we examined the role of SYK in human and experimental DKD. Compared with control tissues, immunostaining of human DKD biopsies showed an accumulation of SYK cells and CD68 macrophages with a very similar localization on serial sections. In a model of streptozotocin-induced type 1 diabetes in hypertensive mice, there was a significant increase in the number of glomerular SYK cells and CD68 cells, with double staining showing that most SYK cells were CD68 macrophages. After 15 wk of diabetes, mice exhibited albuminuria, renal function impairment, glomerulosclerosis, tubular injury, and tubulointerstitial fibrosis. By contrast, diabetic mice with myeloid gene deletion () exhibited a significant reduction in glomerular SYK cell and CD68 macrophage accumulation, glomerulosclerosis, and tubulointerstitial fibrosis-which were associated with reduced mRNA levels of and . However, albuminuria, renal function impairment, and tubular injury were unaffected. In conclusion, we have shown that SYK is predominantly expressed by macrophages in DKD and that SYK facilitates macrophage accumulation and activation in DKD resulting in glomerulosclerosis and tubulointerstitial fibrosis. Spleen tyrosine kinase (SYK) was shown to be mainly expressed by infiltrating kidney macrophages in human and experimental diabetic kidney disease (DKD), suggesting a potential role for SYK in the progression of this disease. Furthermore, myeloid deletion suppressed macrophage recruitment, expression of macrophage elastase (), and development of glomerular and interstitial fibrosis in a mouse model of hypertensive DKD.
Corrigendum for Beenken et al., volume 327, 2024, p. F775-F787.
Am J Physiol Renal Physiol · 2025 Nov · PMID 41196237 · Publisher ↗
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Mechanistic target of rapamycin complex-2 mediates the effect of overnight high K on Kir4.1/Kir5.1 in the DCT and ENaC/ROMK in ASDN.
Duan XP, Zheng JY, Zhang CB … +3 more , Alam S, Wang WH, Lin DH
Am J Physiol Renal Physiol · 2026 Feb · PMID 41191079 · Full text
We examine the role of mTORc2 in mediating overnight-high-K-(HK)-intake-induced stimulation of renal outer medullary K channels (ROMK) in late distal-convoluted-tubule (DCT2)/early connecting-tubule (early-CNT). Also, we...
We examine the role of mTORc2 in mediating overnight-high-K-(HK)-intake-induced stimulation of renal outer medullary K channels (ROMK) in late distal-convoluted-tubule (DCT2)/early connecting-tubule (early-CNT). Also, we explore whether mTORc2 simultaneously inhibits Kir4.1/Kir5.1 and stimulates ROMK/epithelial Na channel (ENaC) during overnight-HK. We performed patch-clamp experiments, immunoblotting, metabolic cage, and in vivo measurement of urinary K excretion in kidney tubule-specific RICTOR (rapamycin insensitive companion of mTOR) knockout mice (Ks-RICTOR-KO) and mice (wild type). Ks-RICTOR-KO mice had a lower urinary K-excretion and higher plasma K concentration than mice. Moreover, overnight HK intake further increased plasma K level in Ks-RICTOR-KO mice but not in mice. Ks-RICTOR-KO mice had higher basolateral Kir4.1/Kir5.1 activity in the DCT than in mice. In contrast, tertiapin-Q (TPNQ)-sensitive K currents (ROMK) were lower in both DCT2/early-CNT and cortical-collecting-duct (CCD) of Ks-RICTOR-KO mice than in mice. Amiloride-sensitive Na currents (ENaC) were significantly lower in DCT2/CNT in Ks-RICTOR-KO mice than in wild type. Overnight HK intake decreased Kir4.1/Kir5.1 activity of DCT and increased amiloride-sensitive Na currents and TPNQ-sensitive K currents in DCT2/early-CNT and in the CCD in mice. However, these effects of overnight-HK were absent in Ks-RICTOR-KO mice. Finally, in vivo measurement of urinary K excretion showed that urinary K excretion in Ks-RICTOR-KO mice on overnight-HK was lower than in mice. In summary, mTORc2 plays a role in maintaining baseline activity of Kir4.1/Kir5.1, ROMK, and ENaC and it mediates the effect of overnight-HK on ENaC and ROMK in aldosterone-sensitive distal nephron (ASDN). We conclude that mTORc2 plays a key role in stimulating renal K excretion during high-K-loading by inhibiting Kir4.1/Kir5.1 in the DCT and stimulating ENaC and ROMK in ASDN. Our study has two novel findings. First, we demonstrate that mTORc2 plays a key role in mediating high-K-intake-induced stimulation of ENaC/ROMK activity in late DCT. Second, we demonstrate that overnight-HK-induced stimulation of kidney K excretion is achieved by simultaneously stimulating ENaC and ROMK in the late DCT, CNT, and CCD, and inhibiting Kir4.1/Kir5.1 in the DCT. Thus, we have illustrated an integrated mechanism by which mTORc2 regulates kidney K excretion.
Maresin 1 modulates renal and cardiac lipid profiles in hypertensive rats.
Bohovyk R, Kravtsova O, Upadhyay G … +5 more , Levchenko V, Lowe M, Shapiro A, Halade GV, Staruschenko A
Am J Physiol Renal Physiol · 2025 Dec · PMID 41159933 · Full text
Chronic inflammation contributes significantly to hypertension and associated target organ damage, particularly in the heart and kidneys. Specialized proresolving mediators, a class of bioactive lipids, play key roles in...
Chronic inflammation contributes significantly to hypertension and associated target organ damage, particularly in the heart and kidneys. Specialized proresolving mediators, a class of bioactive lipids, play key roles in resolving inflammation and maintaining tissue homeostasis. Among them, Maresin 1 (MaR1) has been implicated in cardiovascular regulation and blood pressure control. We hypothesized that MaR1 may mitigate salt-induced hypertension and its related effects in Dahl salt-sensitive (SS) rats. In this study, SS rats were fed a high-salt diet and treated with MaR1. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored. Echocardiography and histology were used to assess cardiac structure, contractility, and fibrosis. Lipidomic profiling quantified inflammation-resolving lipid mediators, and transcriptomic analysis identified organ-specific gene expression changes. MaR1 treatment did not significantly alter MAP, HR, or cardiac structure and function. Echocardiographic and histological evaluations showed no significant changes in cardiac remodeling, contractility, or collagen deposition in the heart or kidney. However, lipidomic profiling revealed shifts in inflammatory lipid mediators, suggesting immunomodulatory and metabolic effects of MaR1. Transcriptomic analysis demonstrated organ-specific gene expression changes, with upregulation of circadian pathways in the heart and modulation of immune signaling in the kidney. Notably, MaR1 influenced circadian blood pressure rhythms, enhancing amplitude and shifting the acrophase, consistent with altered expression of circadian clock genes. Although MaR1 did not affect hypertension development directly, its modulation of lipid metabolism, inflammatory pathways, and circadian regulation suggests therapeutic potential. Future studies should assess longer treatments and combination approaches to clarify its role in cardiorenal disease management. This study shows that MaR1, a specialized proresolving mediator, influences lipid metabolism and modifies gene expression in the heart and kidney in a salt-sensitive hypertension model, without affecting blood pressure or organ structure. These findings highlight the potential role of MaR1 in regulating inflammation and circadian rhythms associated with cardiovascular and renal diseases.
Short-term hypothyroidism impairs the daily oscillations of renal circadian clock and function in a sex-dependent manner.
Kretli-Souza D, Gomes BH, Selvatici-Tolentino L … +9 more , Oliveira-Damasceno Y, Peixoto-Dias AF, Iost AF, de Oliveira LBF, Brunetto EL, Guarnieri LO, Peliciari-Garcia RA, Peruchetti DB, Bargi-Souza P
Am J Physiol Renal Physiol · 2025 Dec · PMID 41143733 · Publisher ↗
Hypothyroidism is associated with the desynchronization of central and peripheral circadian clocks; however, its effects on renal rhythmicity remain unclear. This study investigated the impact of short-term hypothyroidis...
Hypothyroidism is associated with the desynchronization of central and peripheral circadian clocks; however, its effects on renal rhythmicity remain unclear. This study investigated the impact of short-term hypothyroidism on renal molecular clock oscillations and daily kidney function in male and female rats. Hypothyroidism was induced by thyroidectomy followed by methimazole and CaCl administration for 21 days. Renal handling of solutes and electrolytes and the expression of core clock components were evaluated every 6 h over 24 h. Urinary levels of creatinine, protein, glucose, and sodium and the clearance and fractional excretion (FE) of these solutes exhibited circadian oscillations in control rats. In males, hypothyroidism abolished the rhythmicity of serum creatinine, creatinine clearance (C), renal glucose clearance (C), and fractional excretion of glucose, sodium, and potassium; decreased the mesor and amplitude of protein excretion parameters; reduced mesor and amplitude of expression and phase advanced and mRNA expression. In females, hypothyroidism reduced the mesor of urinary creatinine, serum glucose, and CCr while delaying its acrophase; increased the mesor of proteinuria and glucosuria and the mesor and amplitude of C and FE; and disrupted the circadian pattern of FE and and expression in kidney and phase advanced expression. Sodium and potassium daily handlings were more altered in males than in females. No structural damage was found in the kidney of hypothyroid rats. These findings indicate that short-term hypothyroidism desynchronizes the renal circadian clock and disturbs the daily rhythmicity of several renal parameters in a sex-dependent manner, potentially contributing to early-stage kidney dysfunction. Hypothyroidism alters the kidney circadian clock machinery and renal function in a sex-dependent manner, potentially contributing to early-stage kidney dysfunction. Female rats exhibited more severe rhythmic impairments under hypothyroid conditions, including reduced creatinine clearance, increased protein and glucose loss in urine over 24 h, and disrupted circadian oscillations in renal clock components, indicating a greater susceptibility of females to hypothyroidism-induced metabolic disturbances associated with circadian disruption.
The endocytic adaptor ARH facilitates potassium conservation by regulating ROMK and BK.
Al-Qusairi L, Zapf AM, Li D … +2 more , Woodward OM, Welling PA
Am J Physiol Renal Physiol · 2025 Dec · PMID 41138214 · Publisher ↗
Renal outer medullary K (ROMK) channels are essential for urinary potassium secretion, and their endocytosis prevents excessive K loss during dietary deficiency. The clathrin adaptor autosomal recessive hypercholesterole...
Renal outer medullary K (ROMK) channels are essential for urinary potassium secretion, and their endocytosis prevents excessive K loss during dietary deficiency. The clathrin adaptor autosomal recessive hypercholesterolemia (ARH) has been implicated in mediating ROMK internalization, yet its physiological significance remains unclear, as hypokalemia is not reported in patients with type 4 familial hypercholesterolemia (FH4) who lack functional ARH. To address this, we investigated potassium homeostasis in ARH knockout (KO) mice, a model of FH4. Despite conserving K during dietary restriction, ARH-KO mice exhibited exaggerated urinary K loss when challenged with hydrochlorothiazide, consistent with compensatory upregulation of the thiazide-sensitive sodium-chloride cotransporter (NCC). Immunoblotting revealed significantly higher ROMK and large-conductance Ca-activated K channel-α (BKα) protein levels in the renal cortex of ARH-KO compared to wild-type (WT) mice at matched plasma K concentrations. Because BKα contains NPXY motifs required for ARH binding, we confirmed ARH directly associates with BKα by coimmunoprecipitation. Under potassium-deficient conditions, ARH-KO mice showed impaired downregulation of apical ROMK and BKα, indicating ARH-dependent endocytosis. Interestingly, compensatory mechanisms differed by sex: female KO mice exhibited enhanced NCC abundance and phosphorylation, whereas male KO mice showed reduced epithelial sodium channel (ENaC) cleavage and diminished BK auxiliary subunits relative to WT. These findings ) establish ARH as a key regulator of ROMK and BKα trafficking in the distal nephron, ) reveal sex-specific compensatory mechanisms that preserve potassium balance, and ) underscore the delicate nature of K homeostasis upon ARH deletion, with maintained normokalemia at the expense of physiological trade-offs involving altered sodium handling. Renal outer medullary K (ROMK) and large-conductance Ca-activated K channel (BK), both regulated by the clathrin adaptor autosomal recessive hypercholesterolemia (ARH), play essential roles in maintaining potassium balance. Given the life-threatening risks of dyskalemia, it is unsurprising that their activity is controlled by multiple mechanisms, though not without physiological costs. We found that impaired ARH-mediated ROMK and BK internalization triggers activation of alternative potassium-conserving pathways in a sex-specific manner. In females, who are more prone to hypokalemia, this compensation involves thiazide-sensitive sodium-chloride cotransporter (NCC) upregulation, a key player in blood pressure regulation.
Uremic serum exposure leads to differential phenotypic switch in porcine arterial and venous smooth muscle cells.
Su H, Uriyanghai U, Wai C … +11 more , Arteaga EC, Wan H, Adam KP, Sudarsanam VA, Haddad SO, Yang A, Li L, Bahnson EM, Poulton JS, Roy-Chaudhury P, Xi G
Am J Physiol Renal Physiol · 2025 Dec · PMID 41138212 · Full text
Many patients with end-stage kidney disease (ESKD) frequently suffer from both aggressive vascular access stenosis in the venous segment of arteriovenous fistula or arteriovenous graft, and widespread cardiovascular dise...
Many patients with end-stage kidney disease (ESKD) frequently suffer from both aggressive vascular access stenosis in the venous segment of arteriovenous fistula or arteriovenous graft, and widespread cardiovascular disease (CVD) or peripheral arterial disease (PAD). Despite the magnitude of these clinical problems, the pathogenic role of the uremic state in both of these conditions remains unclear. To investigate the underlying mechanisms, we used porcine-derived arterial smooth muscle cells (ApSMCs) and venous smooth muscle cells (VpSMCs) to examine several key aspects of cell behavior in response to uremic serum. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that 30% of uremic serum was able to stimulate the proliferation of both subtypes of cells equally. Cell migration, measured by the scratch assay, showed that uremic serum increased migration of both cells, but was more robust in VpSMCs. Importantly, uremic serum induced phenotypic switching (e.g., dedifferentiation) in both subtypes of cells, as indicated by increased proliferating cell nuclear antigen expression and reduced calponin expression. Intriguingly, we found that several key aspects of this uremia-induced phenotypic switch were stronger in ApSMCs as compared with VpSMCs, including the production of extracellular matrix (ECM) proteins, such as fibronectin, cellular calcification [high expression of RUNX family transcription factor 2 (Runx2), alkaline phosphatase (ALP), and Krüppel-like factor 4 (KLF-4)], and a proinflammatory state [high expression of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6)]. Our findings suggest that uremia plays an important role in both the aggressive arteriovenous stenosis and CVD/PAD that affect many patients undergoing hemodialysis. This information could contribute to the development of novel uremia-specific therapies for both vascular access dysfunction and CVD/PAD in patients with ESKD. This study was the first one to directly explore the differential response of arterial VSMCs and venous VSMCs to uremic serum exposure side by side. Both similarities and differences were detected in this in vitro study, which provides insight into the clinical manifestations we observed in patients with ESKD. Furthermore, these results may also be valuable information for uremia-specific therapies for both vascular access dysfunction and CVD/PAD in patients with ESKD.
Characterization and classification of chronic kidney disease by spatial MIST and deep learning algorithm.
Meah A, Gujarati NA, D'Agati VD … +3 more , Revelo MP, Mallipattu SK, Wang J
Am J Physiol Renal Physiol · 2025 Dec · PMID 41134685 · Full text
Chronic kidney disease (CKD) is characterized by disruption of the native kidney architecture at the cellular and molecular levels, leading to eventual kidney fibrosis. To better resolve the spatial complexity of fibroti...
Chronic kidney disease (CKD) is characterized by disruption of the native kidney architecture at the cellular and molecular levels, leading to eventual kidney fibrosis. To better resolve the spatial complexity of fibrotic remodeling, we applied spatial multiplexed immunostaining with signal tagging (Spatial MIST), a high-dimensional proteomic platform capable of quantifying protein expression at single-cell resolution across intact human kidney tissue specimens. Using kidney biopsies from control/low-grade and high-grade fibrosis, we profiled 22 protein markers to assess structural alterations, cell-type distribution, and spatial relationships across glomerular and interstitial compartments. Spatial proximity analysis revealed fibrosis-associated reorganization of endothelial and epithelial markers, including increased separation between CD31 and β-catenin and altered clustering of podocyte and immune markers. Integration with unsupervised uniform manifold approximation and projection (UMAP) clustering distinguished discrete cell populations, whereas correlation analysis with kidney function metrics revealed that vimentin and alpha smooth muscle actin (α-SMA) positively correlated with fibrosis severity, whereas Wilms tumor 1 (WT1) expression was inversely correlated with declining kidney function. A graph neural network (GNN) classifier trained on spatial proteomic features further identified megalin, WT1, and vimentin as a top predictor of fibrosis grade. Together, these findings demonstrate the utility of Spatial MIST for capturing the molecular heterogeneity of CKD and uncovering spatial signatures of disease progression. This integrative approach provides a foundation for biomarker discovery and spatially informed classification of kidney pathology. In this study, we offer a novel spatial analysis of markers relevant to CKD, which may provide useful insights into disease progression. By using this spatial proximity data, we created a GNN model that is capable of classifying disease severity and identifying markers that are most important for its classification. This integrative approach offers a foundation for future studies aimed at developing clinically actionable tools for CKD diagnosis and prognosis.
Null mutation of the p67phox subunit of NOX2 permits compensatory changes in renal blood flow during the development of salt-sensitive hypertension in SS rats.
Evans LC, Dayton A, Kurth T … +3 more , Anidu BS, Polichnowski AJ, Cowley AW
Am J Physiol Renal Physiol · 2025 Nov · PMID 41115068 · Full text
In the current study, we used SS to assess the involvement of oxidative stress in the regulation of renal blood flow during the development of salt-sensitive hypertension in Dahl salt-sensitive (SS) rats. We performed co...
In the current study, we used SS to assess the involvement of oxidative stress in the regulation of renal blood flow during the development of salt-sensitive hypertension in Dahl salt-sensitive (SS) rats. We performed continuous assessment of mean arterial blood pressure (MAP) and renal blood flow (RBF) over a 2-wk period using radiotelemetry and ultrasound flow probes, respectively. In initial time control studies, we confirmed the stability of the surgical preparation in Sprague-Dawley rats. We next assessed MAP and RBF in male SS and SS during 2 wk of a high-salt (4.0% NaCl) diet. As we have previously shown, the hypertensive response to a high-salt diet was blunted in SS rats compared with SS rats. RBF increased significantly with a high salt in the SS rats. In contrast, although RBF was higher at baseline in SS rats than SS rats, there was no significant increase with high salt in the SS rats. Consequently, by the end of the 2-wk study, renal blood was equivalent in both groups. Using circadian analysis, we found that both MAP and RBF have circadian rhythms. These rhythms were not synchronous at baseline, with the nadir of RBF preceding that of MAP. This separation between rhythms was exacerbated by high salt. In conclusion, using chronic assessment of MAP and RBF, we have shown that when p67 is not functional in SS rats, high-salt causes a significant increase in RBF, and this is associated with a blunted hypertensive response. Continuous measurements of MAP and RBF were made in conscious SS rats to determine the role of oxidative stress in their regulation. Deletion of p67 restored the vasodilatory response to a high-salt diet in SS rats. RBF increased in response to a salt load in SS but not SS rats. Circadian analysis demonstrated that MAP and RBF became asynchronous as the rats progressed through the high-salt challenge: RBF peaked over 4 h before MAP.
Renal tubular (pro)renin receptor deletion exacerbates kidney injury in mice.
Stuart D, Peterson CS, Gopinath D … +3 more , Sundar D, Wheatley W, Ramkumar N
Am J Physiol Renal Physiol · 2025 Nov · PMID 41087039 · Full text
The (pro)renin receptor (PRR) is a multifunctional protein implicated in blood pressure regulation and kidney fibrosis. Previous studies report enhanced PRR expression in nondiabetic and diabetic kidney disease. In this...
The (pro)renin receptor (PRR) is a multifunctional protein implicated in blood pressure regulation and kidney fibrosis. Previous studies report enhanced PRR expression in nondiabetic and diabetic kidney disease. In this study, we investigated whether deletion of renal tubular PRR attenuates kidney injury in type 2 diabetes. Floxed PRR mice were bred with mice expressing Pax8 rtTA and LC1 transgenes and mice (B6.BKS) to obtain renal tubular PRR knockout (KO)- mice. Male, age-matched nondiabetic floxed controls, mice, and PRR KO- mice were studied at 16, 20, 26, and 30 wk of age. PRR KO mice were only studied at 30 wk of age. To induce PRR deletion, PRR KO and PRR KO- mice were treated with 2 mg/mL doxycycline for 12 days at 8-10 wk of age. Compared with controls, mice and PRR KO- mice had higher body weights throughout the study and elevated blood glucose levels at weeks 16 and 20. Compared with controls and mice, PRR KO- mice had higher urine volume, water intake, and urinary albumin excretion. At 30 wk, kidney histology showed minimal tubular or glomerular injury among all four groups. PRR KO mice had elevated expression of tubular injury markers compared with the other three groups. Plasma soluble PRR (sPRR) levels were almost twofold higher in diabetic mice relative to controls with no difference between mice and PRR KO- mice. Renal tubular deletion of PRR does not protect against kidney injury in type 2 diabetes; rather, the loss of PRR impairs baseline tubular function that is exacerbated by type 2 diabetes. We investigated whether renal tubular deletion of the PRR would be protective in mice with type 2 diabetes. Longitudinal assessment to 30 wk of age demonstrated that diabetic mice with deletion of renal tubule PRR had higher albuminuria whereas gene expression of kidney injury markers was elevated in PRR KO mice at baseline compared with diabetic floxed controls and nondiabetic controls. Genetic deletion of PRR results in tubular cell dysfunction that is exacerbated by diabetes.
Acute kidney injury is associated with elevated urinary endotrophin.
Clark AJ, Mendoza Flores B, Saade MC … +7 more , Vu KQ, Pence IJ, Zhang N, An Z, Bu D, Scherer PE, Parikh SM
Am J Physiol Renal Physiol · 2025 Nov · PMID 41083270 · Full text
Acute kidney injury (AKI) is prevalent among hospitalized patients. Novel biomarkers are needed to diagnose AKI and target therapies. Endotrophin (ETP) is a molecule released during collagen type VI formation that may pr...
Acute kidney injury (AKI) is prevalent among hospitalized patients. Novel biomarkers are needed to diagnose AKI and target therapies. Endotrophin (ETP) is a molecule released during collagen type VI formation that may promote injury and fibrosis. Although serum ETP elevation has been associated with adverse outcomes in AKI, urinary ETP has not been assessed in AKI, nor has ETP been evaluated in a pediatric population. Urine samples were collected from a tertiary children's hospital. Medical records were reviewed, and patients who met criteria were sorted into three categories: ) AKI; ) hospitalized controls; and ) outpatient controls. ETP was measured using ELISA, and results were corrected to urine creatinine (uETP:Cre). A multivariate linear regression assessed whether demographic variables were independently associated with uETP:Cre. Odds of AKI were assessed in serial uETP:Cre tertiles using a multivariate logistic regression model that adjusted for patient variables. uETP:Cre was elevated in patients with AKI compared with hospitalized patients without AKI ( < 0.05) and outpatient controls ( < 0.0001). Multivariate analysis revealed that age, but not sex, race, or ethnicity independently correlated with uETP:Cre. After adjustment for these variables, the odds ratio for AKI increased with serial uETP:Cre tertiles. Noninvasive measurement of uETP may deliver meaningful information to aid AKI diagnosis. Given that ETP may be both a biomarker and a clinically actionable stimulus of inflammation and fibrosis, future studies are needed to understand the role of elevated ETP in AKI and whether existing ETP-neutralizing antibodies could represent a new avenue of AKI therapy. Endotrophin (ETP) is a molecule released during the formation of type VI collagen that may promote fibrosis and inflammation. Serum ETP is elevated in acute kidney injury (AKI) and associates with adverse outcomes. Urine ETP during AKI has never been assessed. For the first time, this study demonstrates that urine ETP is also elevated during episodes of AKI, representing a novel, noninvasive AKI biomarker that may be clinically actionable.
Regional metabolic analysis of structurally preserved kidney slices by ex vivo respirometry.
Bessho R, Davidoff O, Kobayashi H … +1 more , Haase VH
Am J Physiol Renal Physiol · 2025 Dec · PMID 41071709 · Full text
A comprehensive spatial analysis of kidney metabolism is essential for advancing knowledge of both normal kidney physiology and pathophysiology. The kidney exhibits marked regional differences in bioenergetic demands and...
A comprehensive spatial analysis of kidney metabolism is essential for advancing knowledge of both normal kidney physiology and pathophysiology. The kidney exhibits marked regional differences in bioenergetic demands and substrate utilization, reflecting the distinct functional profiles of each nephron segment. To complement existing approaches with freshly isolated tubules or primary cell cultures, we established and validated an ex vivo respirometry method using structurally preserved kidney slices on a Seahorse XFe24 platform. This protocol avoids tissue disruption or enzymatic digestion and enables simultaneous, region-specific measurements of metabolic fluxes in the cortex, outer medulla, and inner medulla. It provides an integrated readout of the metabolic properties of the cell types present within each anatomical region. We demonstrate the utility of this approach through proof-of-principle studies that profile region-specific metabolic fluxes under hyperglycemic conditions in a mouse model of obesity and type 2 diabetes, as well as the metabolic alterations that accompany the transition from acute ischemic injury to chronic kidney disease. Furthermore, to highlight its relevance for therapeutic discovery, we applied this method to assess the impact of pharmacological hypoxia-inducible factor activation on regional kidney bioenergetics. In summary, this protocol advances the study of kidney metabolism by providing a robust platform for region-specific analysis of kidney respiration and bioenergetics and holds promise for accelerating the development of novel therapies targeting metabolic pathways in kidney disease. Assessment of regional metabolism in kidney tissue is crucial for understanding normal physiology and disease. We have developed a robust ex vivo method to measure respiration in structurally preserved kidney slices using a metabolic flux analyzer. This approach enables analysis of metabolic fluxes and substrate utilization in the kidney cortex, outer medulla, and inner medulla while maintaining tissue architecture, providing region-specific insights into kidney metabolism with broad applications in disease modeling and therapeutic discovery.
5-Hydroxytryptamine 1F receptor loss reduces renal vasculature and prevents lasmiditan-induced recovery following moderate-severe acute kidney injury in mice.
Thompson AD, McAlister KW, Scholpa NE … +4 more , Janda J, Hortareas J, Georgieva TG, Schnellmann RG
Am J Physiol Renal Physiol · 2025 Dec · PMID 41060776 · Full text
Kidney disease (KD) has emerged as a major global health crisis and leading cause of morbidity and mortality worldwide, impacting over 850 million individuals. Pathophysiological hallmarks of KD encompass renal tubular c...
Kidney disease (KD) has emerged as a major global health crisis and leading cause of morbidity and mortality worldwide, impacting over 850 million individuals. Pathophysiological hallmarks of KD encompass renal tubular cell injury/necrosis, tubulointerstitial fibrosis, vascular dysfunction/rarefaction, and mitochondrial dysfunction, all of which are implicated in disease initiation/progression. Unfortunately, there remains a general lack of effective Food and Drug Administration (FDA)-approved therapeutics for the treatment of KD. Thus, the identification of novel and/or repurposed treatment strategies remains of dire importance. Previously, we identified the 5-hydroxytryptamine 1F receptor (HTR1F) as a modulator of renal mitochondrial homeostasis and demonstrated that mice lacking this receptor exhibit hindered renal recovery following mild ischemia/reperfusion-induced acute kidney injury (I/R-AKI). In addition, we reported that treatment with the HTR1F agonist lasmiditan, an FDA-approved therapeutic for acute migraines, expedites renal recovery following I/R-AKI in mice. Here, we show that lasmiditan treatment following moderate-severe I/R-AKI ameliorates acute tubular injury, mitochondrial dysfunction, tubulointerstitial fibrosis, and vascular rarefaction in the renal cortex of mice, which likely contributes to the enhanced recovery observed. Importantly, we also confirm that this lasmiditan-induced renal recovery is contingent on expression. Furthermore, mice lacking the HTR1F exhibit decreased innate renal cortical vasculature, exacerbated rarefaction, and markedly increased mortality rates following moderate-severe I/R-AKI. These findings not only underscore the importance of expression and agonism in renal repair and recovery but also further highlight the repurposing potential of lasmiditan for the treatment of AKI and/or KD onset/progression. In the present study, we confirmed that lasmiditan-induced renal recovery following moderate-severe bilateral ischemia/reperfusion-induced acute kidney injury (I/R-AKI) in mice is dependent on the expression. Furthermore, lasmiditan treatment ameliorated acute tubular injury, mitochondrial dysfunction, tubulointerstitial fibrosis, and renal cortical vascular rarefaction postinjury, likely contributing to this enhanced recovery. Interestingly, we also found that mice lacking the HTR1F display decreased innate renal cortical vasculature, exacerbated rarefaction, and exhibit markedly increased mortality following moderate-severe I/R-AKI.
Pregnane X receptor increases urine concentration by upregulating hypothalamic arginine vasopressin expression.
Sun X, Li R, Luan Z … +15 more , Ma B, Xu H, Luo T, Hu Y, Zhao W, Qiao R, Du C, Cao J, Zhou H, Guo Y, Zhong J, Zhang Y, Yang B, Guan Y, Zhang XY
Am J Physiol Renal Physiol · 2025 Nov · PMID 41052029 · Publisher ↗
The pregnane X receptor (PXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. PXR is constitutively expressed in the hypothalamus and kidney, with its physiological function i...
The pregnane X receptor (PXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. PXR is constitutively expressed in the hypothalamus and kidney, with its physiological function incompletely understood. In this study, we found that treatment with pregnenolone-16α-carbonitrile (PCN), an endogenous PXR ligand, significantly reduced urine volume and increased urine osmolarity in C57BL/6 mice. In contrast, PXR gene knockout () mice exhibited impaired urine-concentrating ability, leading to a polyuria phenotype. In addition, treatment of mice with PCN significantly upregulated, whereas PXR gene deficiency substantially reduced, arginine vasopressin (AVP) expression in the hypothalamus. Bioinformatic analysis showed that the mouse AVP gene promoter contains a putative PXR response element (PXRE). The luciferase reporter, ChIP, and electrophoretic mobility shift assays further revealed that PXR can bind to the PXRE, resulting in a significant increase in AVP gene transcription. Collectively, the present study demonstrates that hypothalamic PXR plays a critical role in regulating urine volume, and its activation enhances urine-concentrating capacity primarily by upregulating the expression of AVP in the hypothalamus. Activation of PXR enhances urine concentration, whereas PXR deficiency diminishes this capacity. PXR is coexpressed with AVP in the hypothalamus, where it upregulates AVP transcription to promote renal water reabsorption. These findings reveal a novel role for PXR in regulating urinary concentration and propose its potential as a therapeutic target for water metabolism disorders, such as diabetes insipidus.
Inducible knockout mouse line.
Khan S, Chen L, Chou CL … +2 more , Khundmiri SJ, Knepper MA
Am J Physiol Renal Physiol · 2025 Dec · PMID 41052028 · Full text
Arginine vasopressin (AVP) is a peptide hormone synthesized in the hypothalamus and secreted by the posterior pituitary. Previous studies toward understanding AVP physiology relied heavily on Brattleboro rats, which have...
Arginine vasopressin (AVP) is a peptide hormone synthesized in the hypothalamus and secreted by the posterior pituitary. Previous studies toward understanding AVP physiology relied heavily on Brattleboro rats, which have a spontaneous mutation in the gene and lack circulating AVP. However, these rats are difficult to breed due to high neonatal death and behavioral issues, causing commercial breeders to stop production. To address this, we developed a mouse line with tamoxifen-inducible deletion of . We used CRISPR/Cas9 to insert loxP sites into the gene. These mice were then bred with mice expressing a tamoxifen-inducible Cre recombinase. The resulting conditional knockout mice (Cre) are viable, fertile, and healthy before induction. Administration of tamoxifen in 8-12-wk-old mice successfully deleted , as confirmed by Sanger sequencing. This deletion caused a significant decrease in urine osmolality, a hallmark of AVP deficiency. The kidney structure remained normal, with no signs of medullary atrophy. In addition, these mice exhibited a substantially decreased expression of the aquaporin 2 water channel (AQP2), which is involved in water reabsorption in the kidney inner medulla. We illustrate the use of this model by using RNA-seq to profile the consequences of deletion on gene expression in the kidney. The curated RNA-seq data can be browsed, searched, or downloaded at https://esbl.nhlbi.nih.gov/Databases/AVP-KO/. In conclusion, we successfully created an inducible knockout mouse line that has been made available to the research community. This model will be valuable for studying water balance regulation, polycystic kidney disease, and the neural, vascular, and metabolic functions of vasopressin. We developed an inducible knockout mouse line that will be shared with the research community and is likely to be useful for further study of the regulation of water balance and polycystic kidney disease, as well as neural, vascular, and metabolic roles of vasopressin.
Decreased parietal epithelial cell density is linked to podocyte depletion and predictors of kidney disease progression in human kidneys.
Ference-Salo JT, O'Connor CL, Menon R … +4 more , Otto EA, Dailey M, Bitzer M, Beamish JA
Am J Physiol Renal Physiol · 2025 Nov · PMID 41052018 · Full text
Parietal epithelial cells (PECs) have been implicated in the pathogenesis of glomerulosclerosis in rodent models, and novel technologies are beginning to unravel their contributions to human glomerular disease. Here, we...
Parietal epithelial cells (PECs) have been implicated in the pathogenesis of glomerulosclerosis in rodent models, and novel technologies are beginning to unravel their contributions to human glomerular disease. Here, we report the development, validation, and application of a deep learning approach to analyze the PEC population in over 14,000 glomeruli from nephrectomy samples from patients with minimal overt chronic kidney disease (CKD). This analysis revealed a striking correlation between PEC density and podocyte density. Reduced PEC density was also associated with aging and the presence of diabetes. Furthermore, the PEC density in normal-appearing glomeruli was associated with the frequency of glomerular pathology, including global and segmental glomerulosclerosis, in the same patient sample. Patients with low PEC density had gene expression changes consistent with cellular stress in PECs. These observations support a link between PEC population and the progression of CKD. Little is known about the contribution of PECs to human chronic glomerular disease. We developed, validated, and deployed deep learning image analysis tools to analyze the relationship between PECs and clinical and histopathologic risks of glomerular disease progression in human nephrectomy samples. These analyses revealed a novel link between PEC depletion and early evidence of chronic glomerular disease. The tools developed can be applied to many applications in the study of human kidney disease.
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