American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Pannexin channels in the kidney.
Williams MD, O'Donnell BL, Columbus L … +3 more , DeLalio LJ, Erdbrügger U, Isakson BE
Am J Physiol Renal Physiol · 2025 Nov · PMID 41042800 · Full text
Renal dysfunction leads to critical health conditions, including acute kidney injury (AKI) and chronic kidney disease (CKD), and is a driver of hypertension. Despite their global prevalence and impact, the pathophysiolog...
Renal dysfunction leads to critical health conditions, including acute kidney injury (AKI) and chronic kidney disease (CKD), and is a driver of hypertension. Despite their global prevalence and impact, the pathophysiology for all kidney disease subtypes is incompletely understood; therefore, many patients progress to kidney failure, needing dialysis and transplantation. This review highlights the role of pannexins-a family of channel-forming glycoproteins-in renal physiology and pathophysiology. Compared with other organ systems such as the brain and cardiovascular system, relatively little is known about the function of pannexins in the kidney. However, recent findings indicate that pannexins may be potential therapeutic targets in the treatment of hypertension, AKI, and CKD, though further research is needed to fully understand their precise role in renal health and disease.
The nonsteroidal MR antagonist finerenone reverses Western diet-induced kidney disease by regulating mitochondrial and lipid metabolism and inflammation.
Myakala K, Wang XX, Shults N … +11 more , Hughes EP, de Carvalho Ribeiro P, Penjweini R, Link K, Barton K, Krawczyk E, Clarkson Paredes C, Popratiloff A, Knutson JR, Cowart AL, Levi M
Am J Physiol Renal Physiol · 2025 Nov · PMID 41021758 · Full text
Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the...
Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the beneficial kidney effects of the nonsteroidal MR antagonist finerenone (FN) in a mouse model of Western diet-induced obesity and insulin resistance. Ten-week-old male C57BL/6J mice were fed a low-fat (LF) or a Western diet (WD) for 12 weeks followed by treatment with either vehicle or FN for another 14 weeks (intervention studies) until they were 36 weeks old. Finerenone treatment prevented ) the increased albuminuria and kidney injury molecule 1 (KIM1); ) the expanded extracellular mesangial matrix and synaptopodin coverage; ) fibronectin, collagen IV, CD45, and CD68 immunostaining; ) glomerular basement membrane disruption, podocyte foot processes effacement, and mitochondrial structural abnormalities; ) the proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1)], innate immunity pathways [Toll-like receptor-2 (TLR2), stimulator of interferon genes (STING), signal transducer and activator of transcription 3 (STAT3)], and fibrosis markers fibronectin, transforming growth factor-β (TGFβ), and plasminogen activator inhibitor-1 (Pail); and ) the increased kidney cholesterol levels. There was also reduced expression of nuclear receptor estrogen-related receptor-γ (ERRγ) without changes in ERRα in WD-fed mice, whereas both ERRα and ERRγ expression levels increased after finerenone treatment. NADH lifetime analysis showed decreased bound NADH, compatible with decreased mitochondrial oxidative phosphorylation (OXPHOS) in the kidneys of WD-fed mice compared to controls, which was prevented by finerenone treatment. In conclusion, finerenone treatment exhibits a renal protective role and prevents the progression of kidney disease by regulating mitochondrial function, most likely via ERRγ, and reducing lipid accumulation and inflammation. Finerenone, a nonsteroidal mineralocorticoid receptor (MR) antagonist, has shown promise in protecting against kidney damage in obese, insulin-resistant mice. It effectively prevents albuminuria, inflammation, fibrosis, and mitochondrial dysfunction, while also restoring estrogen-related receptor-γ (ERRγ) expression. These results suggest that finerenone could play a key role in halting the progression of kidney disease by enhancing mitochondrial function and reducing harmful lipid accumulation, offering a potential therapeutic strategy for managing kidney complications in metabolic disorders.
Sex differences in renal acid-base regulation.
Dominguez Rieg JA, Odgaard LN, Xue J … +5 more , Nogueira Coelho J, Harris AN, Thomas L, Fenton RA, Rieg T
Am J Physiol Renal Physiol · 2025 Nov · PMID 41015430 · Full text
Transport across cells of the renal tubule differs between females and males, possibly as a consequence of varying abundance of transport proteins along the nephron. We hypothesized that sex-specific differences in the p...
Transport across cells of the renal tubule differs between females and males, possibly as a consequence of varying abundance of transport proteins along the nephron. We hypothesized that sex-specific differences in the physiological responses and in transport protein abundances exist in the context of acid-base challenges. We used female and male C57Bl/6J mice and challenged them with acid (NHCl) or base (NaHCO) in their drinking water for 8 days. Blood and urine samples were collected at baseline and at the end of the experimental period before kidneys were harvested and protein abundances determined. In response to NHCl challenge, the significant decreases in urine pH, blood HCO, and base excess were similar in both sexes despite a smaller intake of NHCl in male compared with female mice. In response to NaHCO challenge, urine pH significantly increased in both sexes; however, blood pH, HCO, and base excess were increased significantly and to a greater extent in male compared with female mice. Two-way analysis of variance demonstrated that out of the 12 tested proteins, 7 were significantly affected by sex, 7 were significantly affected by treatment, and the interaction of sex and treatment was significant for Na/K/2Cl cotransporter, NKCC2. In summary, our study demonstrates ) sex differences in protein abundance, ) proteins are affected differentially in response to acid-base challenges, and ) NKCC2 is a new and potentially important player in acid-base regulation. Disturbances in acid-base regulation are common and can have detrimental effects. Here, we provide evidence that acid-base disturbances in males and females are consistent with female mice being able to defend acid and base challenges more effectively. Our data have potential clinical importance in humans regarding the treatment of acidosis and alkalosis in males versus females.
Diurnal function and expression of aquaporins in the mouse kidney.
Nguyen H, Huynh NV, Hyndman KA
Am J Physiol Renal Physiol · 2025 Nov · PMID 41006065 · Full text
Aquaporins (AQPs) are a family of water channels found throughout the body and in the kidney; they function in maintaining water homeostasis. The insertion of AQPs into the plasma membrane of the kidney cells drives wate...
Aquaporins (AQPs) are a family of water channels found throughout the body and in the kidney; they function in maintaining water homeostasis. The insertion of AQPs into the plasma membrane of the kidney cells drives water reabsorption back into the circulation, and the concentration of the urine involves AQP2 apical localization in the collecting duct principal cells. Kidney functions, like glomerular filtration rate (GFR) and urine flow, are significantly greater during the active period compared with the inactive period when sleeping. We hypothesized that there is a diurnal pattern in urine and/or plasma osmolality and that this reflects changes in kidney aquaporins in mice. Male and female C57BL/6J mice were studied in the middle of their active period [zeitgeber time (ZT) 18] or the middle of their inactive period (ZT6). We confirmed GFR was greater at ZT18 compared with ZT6. Urine and plasma osmolality were significantly greater at ZT18 in both sexes. Although ∼18% of kidney RNA had a diurnal pattern, the changes observed in the genes did not reflect protein abundance differences where nephron AQP1, AQP2, and AQP4 abundance were greater at ZT18 compared with ZT6. In conclusion, diurnal variability in plasma osmolality and urine-concentrating ability is likely driven by time-of-day changes in intake, greater GFR, and establishment of the medullary interstitial gradient during the active period. Greater nephron aquaporins in the middle of the active period may function to reabsorb water while the kidney excretes excess solutes to dilute the plasma osmolality and maintain fluid-electrolyte balance. Mouse plasma and urine osmolalities are greater in the middle of the active period, when food/water intake, gut reabsorption, glomerular filtration rate, and urine flow are increased. There were time-of-day effects on aquaporin mRNA, and increased nephron abundance of aquaporins during the middle of the active period. As the kidneys excrete the excess solutes, the medullary interstitial gradient and aquaporins are primed to concentrate the urine and return the plasma osmolality to a steady state.
Underlying metabolic syndrome exacerbates induced acute kidney injury via systemic Th17/Treg dysregulation.
More MP, Saha P, Roy S … +2 more , Trivedi A, Chatterjee S
Am J Physiol Renal Physiol · 2025 Nov · PMID 40987520 · Publisher ↗
Climate change has led to a rise in infections, while the global obesity epidemic has increased susceptibility to severe bacterial infections. Obesity and high-fat diet (HFD) consumption promote systemic inflammation an...
Climate change has led to a rise in infections, while the global obesity epidemic has increased susceptibility to severe bacterial infections. Obesity and high-fat diet (HFD) consumption promote systemic inflammation and immune dysregulation, which may exacerbate sepsis and its complications, including acute kidney injury (AKI). This study investigates the mechanistic role of HFD-induced metabolic dysfunction in sepsis-associated AKI. Adult C57BL/6J mice were placed on a standard CHOW diet or a 60% kcal HFD for 6 wk before infection. infection was induced via intragastric administration by oral gavage of 10 colony-forming units of suspended in PBS. Kidney function was assessed, and kidney tissues were analyzed for markers of inflammation, oxidative stress, and necrosis. Systemic Th17/Treg ratios were determined. In vitro, renal proximal tubular epithelial cells were treated with leptin and IL-17A with/without an IL-17 receptor antagonist to confirm the role of IL-17 signaling in renal epithelial cell pathology. A proinflammatory Th17/Treg imbalance, along with a marked increase in renal TLR4 activation, inflammation, and necrosis, was observed in the HFD + infection group. In vitro studies confirmed that IL-17 and leptin synergistically activate the NF-κB pathway, promoting inflammatory cytokine release. These findings indicate that HFD-induced metabolic stress exacerbates sepsis-associated AKI. The interplay between IL-17 signaling and leptin may further amplify renal injury, underscoring the need for targeted interventions. Strategies to modulate IL-17 signaling and metabolic inflammation may offer novel therapeutic approaches to reduce AKI severity in obese individuals with bacterial sepsis. This study reveals that high-fat diet (HFD)-induced metabolic dysfunction exacerbates sepsis-associated acute kidney injury (AKI) via TLR4-driven inflammation, oxidative stress, and systemic Th17/Treg imbalance. Novel in vitro findings show that IL-17 and leptin synergistically activate NF-κB signaling in renal epithelial cells, amplifying inflammation, which is mitigated by IL-17 receptor blockade. These results highlight IL-17 signaling as a potential therapeutic target for reducing AKI severity in obese individuals with bacterial sepsis.
A key role of AT receptors and Na/H exchanger 3 in the proximal tubules in angiotensin II-induced and two-kidney, one-clip Goldblatt hypertension.
Li XC, Hassan R, Zhuo JL
Am J Physiol Renal Physiol · 2025 Nov · PMID 40987504 · Full text
The present study tests the hypothesis that dual deletion of AT receptors and Na/H exchanger 3 (NHE3) selectively in the proximal tubules further attenuates angiotensin II (Ang II)-induced and two-kidney, one-clip (2K1C)...
The present study tests the hypothesis that dual deletion of AT receptors and Na/H exchanger 3 (NHE3) selectively in the proximal tubules further attenuates angiotensin II (Ang II)-induced and two-kidney, one-clip (2K1C) Goldblatt hypertension. Proximal tubule (PT)-specific AT receptor and NHE3 double knockout mice, PT-/, were generated using the iL-/ approach. Male and female wild-type (WT) and PT-/ double knockout mice were infused with a pressor dose of Ang II for 2 wk (1.5 mg/kg body wt/day ip) or induced with 2K1C Goldblatt hypertension for 4 wk. In wild-type (WT) mice, basal systolic blood pressure (SBP) was 118 ± 3 mmHg ( = 9), which increased to 161 ± 3 mmHg in response to Ang II infusion ( < 0.01, = 10) or to 136 ± 3 mmHg in response to induction of 2K1C Goldblatt hypertension ( = 12, < 0.01). By comparison, basal SBP was 13 ± 2 mmHg lower in PT- ( < 0.01) or in PT- single-gene knockout mice than WT mice ( < 0.01). Double deletion of AT and NHE3 in the proximal tubules further lowered basal SBP by 6 ± 2 mmHg in PT-/ mice ( < 0.05). In response to Ang II infusion, SBP increased to 121 ± 3 mmHg in PT-/PT- mice ( < 0.01). 2K1C Goldblatt hypertension was attenuated in PT- (108 ± 3 mmHg, < 0.01, = 10), PT- (110 ± 2 mmHg, < 0.01, = 10), or PT-/ mice (103 ± 2 mmHg, < 0.01, = 8), respectively. Taken together, our study provides further evidence for a key role of proximal tubule AT receptors and NHE3 in the development of Ang II-induced and 2K1C Goldblatt hypertension. This study generates a novel mouse model with double deletion of AT receptors and Na/H exchanger 3 (NHE3) in the proximal tubules to directly determine their role in the development of Ang II-induced and two-kidney, one-clip (2K1C) Goldblatt hypertension. This study provides further evidence for a key role of proximal tubule AT receptor and NHE3 not only in maintaining physiological blood pressure homeostasis but also in the development of Ang II-induced and 2K1C Goldblatt hypertension.
Therapeutic potential of tubular serine protease inhibitors in proteinuria.
Boes MB, Svenningsen P, Hinrichs GR … +2 more , Bistrup C, Jensen BL
Am J Physiol Renal Physiol · 2025 Dec · PMID 40982254 · Publisher ↗
Proteinuria is both a predictor and mediator of chronic kidney disease (CKD) progression, but treatment options targeting its underlying mechanisms are limited. Emerging evidence suggests that aberrantly filtered serine...
Proteinuria is both a predictor and mediator of chronic kidney disease (CKD) progression, but treatment options targeting its underlying mechanisms are limited. Emerging evidence suggests that aberrantly filtered serine proteases contribute to the pathogenesis of proteinuria and progressive kidney injury through multiple pathways, including podocyte injury, inappropriate activation of the epithelial sodium channel (ENaC), and tubular complement activation. Serine protease inhibitors, such as aprotinin, camostat mesylate, and nafamostat mesylate, as well as off-target effects of amiloride, have shown promise in preclinical and early clinical studies by mitigating these pathological processes. These drugs reduce proteinuria, sodium retention, oxidative stress, inflammation, and fibrosis. However, clinical translation is hindered by limited data from controlled trials, varying pharmacokinetics, and concerns about systemic adverse effects and long-term safety. Endogenous serine protease inhibitors help maintain proteolytic balance in the kidneys, but their capacity may be overwhelmed in proteinuria. Although complete inhibition could disrupt essential functions, pharmacologic modulation of tubular serine protease activity may be a more effective strategy by preserving beneficial activity while limiting pathological effects. This review synthesizes current knowledge on the pathophysiological role of tubular serine proteases and evaluates the therapeutic potential of their inhibition as a potential target in proteinuric diseases. We identify key knowledge gaps, including the need for mechanistic pharmacodynamic trials, biomarker-guided patient selection using urinary serine protease activity, and long-term efficacy and safety studies. Serine protease inhibitors are a promising, underexplored therapeutic strategy in proteinuric conditions that may complement existing treatments by targeting specific pathogenic mechanisms involved in disease progression.
Retraction for Sakairi et al., volume 298, 2010, p. F557-F567.
Am J Physiol Renal Physiol · 2025 Oct · PMID 40961366 · Publisher ↗
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Sorting nexins associated with recycling complexes regulate epithelial sodium channel trafficking.
Scott ML, Cheung TT, Logue MJE … +3 more , Zheng F, Hamilton KL, McDonald FJ
Am J Physiol Renal Physiol · 2025 Nov · PMID 40952999 · Publisher ↗
In the kidney, the epithelial sodium channel (ENaC) facilitates sodium absorption in polarized epithelia and is required to maintain salt and water homeostasis. ENaC's apical membrane population is strictly controlled, w...
In the kidney, the epithelial sodium channel (ENaC) facilitates sodium absorption in polarized epithelia and is required to maintain salt and water homeostasis. ENaC's apical membrane population is strictly controlled, with loss of this control leading to hyper- or hypotensive disorders such as Liddle's syndrome or pseudohypoaldosteronism type 1, respectively. Retromer and retriever are conserved endosome-localized protein trafficking complexes that mediate recycling of membrane proteins to the cell surface either directly, via recycling endosomes, or via the trans-Golgi network. Protein cargo for recycling is linked to retromer or retriever by sorting nexin (SNX) proteins. We hypothesized that SNX proteins are required for ENaC recycling. Using two epithelial cell lines [Fischer rat thyroid (FRT) and mouse cortical collecting duct clone 1 (mCCDcl1)] and the human embryonic kidney 293 (HEK293) cell line, with transient transfection of human ENaC-encoding plasmids into HEK293 and FRT epithelia, we found that siRNA knockdown of retromer- and retriever-associated sorting nexin (SNX1, 2, 3, 5, and 17) proteins reduced ENaC amiloride-sensitive short-circuit current and reduced ENaC cell surface population, observed using cell surface biotinylation. Coimmunoprecipitation experiments using transiently transfected human ENaC demonstrated a protein-protein interaction with SNX3 in FRT cells and with SNX17 in both FRT and HEK293 cells, suggesting that SNX3 and SNX17 act as cargo binding proteins between ENaC and the retromer and retriever complexes, respectively. Together, our findings suggest that SNX proteins associated with both the retromer and retriever recycling complexes play a role in maintaining ENaC cell surface populations in polarized epithelia. Cell surface levels of the epithelial sodium channel, ENaC, are controlled by endocytosis and exocytosis pathways. Sorting nexin (SNX) family members facilitate the binding of protein cargo to recycling complexes for sequestration into recycling compartments. We show that knockdown of several SNX proteins decreases ENaC current and cell surface population, and both SNX3 and SNX17 coimmunoprecipitate with ENaC. Our data provide new insights into the control of ENaC cell surface levels and activity.
Electron paramagnetic resonance imaging to detect acute kidney injury.
Kishimoto S, Horie K, Devasahayam N … +8 more , Yamashita K, Chandramouli GVR, Yamamoto K, Brender JR, Mitchell JB, Krishna MC, Linehan WM, Crooks DR
Am J Physiol Renal Physiol · 2025 Nov · PMID 40939023 · Full text
Renal oxygenation is essential for maintaining kidney function. Disruptions in oxygen delivery can lead to renal hypoxia, which can exacerbate kidney injury through multiple pathways, including inflammation, oxidative st...
Renal oxygenation is essential for maintaining kidney function. Disruptions in oxygen delivery can lead to renal hypoxia, which can exacerbate kidney injury through multiple pathways, including inflammation, oxidative stress, and ischemia-reperfusion injury. Despite the recognized importance of oxygenation in renal pathology, noninvasive and reliable methods for assessing kidney oxygen levels are limited. Current techniques either lack sensitivity or involve invasive procedures, restricting their use in routine monitoring. Therefore, there is a pressing need for innovative approaches to map renal oxygenation, particularly in kidney injury. This study evaluated electron paramagnetic resonance (EPR)-based oxygen imaging using the paramagnetic tracer Ox071 to map kidney oxygen levels in mice with cyclophosphamide-induced kidney injury. Urine partial pressure of oxygen (Po) was also assessed as a potential surrogate marker. EPR oximetry accurately measured kidney oxygen distribution, revealing a temporary increase in Po post-injury. Urine oximetry, however, did not reliably reflect changes in kidney oxygenation. Furthermore, EPR oximetry provided high-resolution spatial mapping of oxygen levels within the kidney, allowing for a detailed understanding of the impact of hypoxia on renal tissue. EPR oximetry is a promising, noninvasive tool for monitoring renal oxygenation, offering high-resolution mapping and longitudinal assessment. Its ability to provide detailed information about oxygen distribution within the kidney makes it a valuable tool for studying the pathophysiology of renal diseases and for developing novel therapeutic strategies. Quantitative spatially resolved measurement of renal oxygenation has the potential to guide clinical decision making in renal disorders such as acute kidney injury. In this study, we demonstrate the utility of electron paramagnetic resonance imaging to provide noninvasive and quantitative high-resolution mapping of kidney oxygen concentrations.
Effects of propofol and sevoflurane anesthesia on renal blood flow and oxygenation during major hemorrhage in pigs.
Frithiof R, Taavo M, Emami A … +1 more , Franzén S
Am J Physiol Renal Physiol · 2025 Oct · PMID 40939017 · Publisher ↗
Hemorrhage and hypotension leading to renal hypoperfusion are common causes of acute kidney injury (AKI). Anesthetic agents may affect renal hemodynamics, potentially altering renal outcomes during hypovolemia. This stud...
Hemorrhage and hypotension leading to renal hypoperfusion are common causes of acute kidney injury (AKI). Anesthetic agents may affect renal hemodynamics, potentially altering renal outcomes during hypovolemia. This study evaluated the effects of two commonly used anesthetics, propofol and sevoflurane, on renal blood flow (RBF) and oxygenation during hemorrhage. Fourteen pigs (30 ± 2 kg) were anesthetized with either propofol or sevoflurane, with fentanyl as an opioid supplement in both groups. Following baseline measurements, hemorrhage was induced to maintain a mean arterial pressure (MAP) below 50 mmHg for 30 min, after which resuscitation was performed using a 1:1 replacement of whole blood and Ringer's acetate. Acute renal function recovery was evaluated 1 h post resuscitation. At baseline, sevoflurane-anesthetized animals had lower RBF and renal oxygen delivery, and higher renal vascular resistance compared with the propofol group. During hemorrhage, the change in these variables was comparable. After resuscitation, cardiovascular and RBF recovery were similar between the groups. However, oxygen delivery remained significantly lower in the sevoflurane group compared with the propofol group. In addition, renal vascular resistance was significantly higher during sevoflurane anesthesia compared with propofol after recovery. In conclusion, compared with propofol anesthesia, sevoflurane anesthesia reduced RBF and renal oxygen delivery already at baseline. The difference in oxygen delivery persisted after hemorrhage, even though RBF was comparable between groups. In a pig model of major hemorrhage, we investigated whether the choice of anesthetic agent impacts renal blood flow and oxygen delivery after hemorrhage. The volatile anesthetic sevoflurane reduced renal blood flow and oxygen delivery compared with the intravenous agent propofol before hemorrhage. Following hemorrhage, oxygen delivery remained lower, accompanied by sustained renal vasoconstriction, in subjects anesthetized with sevoflurane compared with those anesthetized with propofol.
Dietary K supplementation restores normal aldosterone level in Na-deprived renal tubule-specific CAP1/Prss8-deficient mice.
Ehret E, Auberson M, Wang D … +2 more , Staub O, Hummler E
Am J Physiol Renal Physiol · 2025 Oct · PMID 40938892 · Publisher ↗
We previously reported that Na-deprived mice lacking CAP1/Prss8 in kidney tubules maintained epithelial sodium channel-mediated sodium balance albeit persistent hypoaldosteronism, hence indicating an uncoupling from aldo...
We previously reported that Na-deprived mice lacking CAP1/Prss8 in kidney tubules maintained epithelial sodium channel-mediated sodium balance albeit persistent hypoaldosteronism, hence indicating an uncoupling from aldosterone production. This further suggested an implication of the serine protease CAP1/Prss8 (prostasin) in the cross talk of the kidney with the adrenal gland that does not express prostasin. When these knockout (Ko) mice were additionally exposed to a high K diet, plasma K levels and plasma aldosterone concentrations were normalized and no longer different from those of the control mice. The mRNA transcript expression of the adrenal aldosterone synthase which was lower in Na-deprived Ko animals, was in the normal range. Plasma aldosterone levels were similar to control animals, indicating that K rescued the hypoaldosteronism in Na-deprived Ko animals. These data suggest that CAP1/Prss8 (prostasin) is implicated in the regulation of aldosterone synthesis or production and that the consequences of deficiency can be compensated by high dietary K supplementation. Prostasin may therefore present a promising regulator of aldosterone production by affecting the adrenal steroidogenic pathway. We explore the role of the serine protease CAP1/Prss8 in aldosterone synthesis. Described previously as a candidate gene for hypertension, the mechanism by which renal serine protease deficiency is implicated in aldosterone production is still largely unknown. Our findings underscore a role of prostasin in the regulation of aldosterone synthesis. In kidney-specific knockout mice, K supplementation is predominant over Na and restores normal aldosterone production proposing new pathways to treat hypo- or hypertension.
SerpinE2 deficiency exacerbates glomerular injury in diabetic nephropathy through dysregulated angiogenesis and inflammatory responses.
Idir L, Yu J, Bonnin P … +5 more , Richard B, Loyau S, Boulaftali Y, Bouton MC, Arocas V
Am J Physiol Renal Physiol · 2025 Oct · PMID 40897517 · Publisher ↗
Diabetic nephropathy (DN) is a multifactorial disease in which inflammation and angiogenesis play a crucial role. SerpinE2, or protease nexin-1 (PN-1), is a protease inhibitor of the serpin family, expressed by vascular...
Diabetic nephropathy (DN) is a multifactorial disease in which inflammation and angiogenesis play a crucial role. SerpinE2, or protease nexin-1 (PN-1), is a protease inhibitor of the serpin family, expressed by vascular and inflammatory cells. In this study, we addressed the role of SerpinE2 in DN, using the models of streptozotocin-induced type-1 and db/db type-2 diabetes. Our results indicated that SerpinE2 diabetic mice presented histological features of an aggravated nephropathy compared with wild-type (WT) mice, with higher hypertrophy of glomeruli, greater collagen IV accumulation, and reduced nephrin expression. Moreover, renal function was worsened in SerpinE2 diabetic mice with urine albumin-to-creatinine ratio much higher compared with WT. Consistent with the previously demonstrated antiangiogenic properties of SerpinE2, we observed that glomerular vascularization was higher in SerpinE2 than in WT diabetic mice in early type-1 diabetes, associated with increased proliferation of glomerular cells. Accordingly, renal blood flow reduction in response to diabetes was lower in SerpinE2 mice than in WT mice. In addition, we measured higher mRNA levels of inflammatory cytokines and of midkine in the kidneys of diabetic mice compared with WT mice. Altogether, our results indicate that SerpinE2 may play a protective role in the development of DN by limiting glomerular damage throughout regulation of early process in angiogenesis and inflammation. In two different models of diabetes, SerpinE2 deficiency exacerbated nephropathy, as evidenced by increased glomerular hypertrophy and collagen expression, reduced nephrin, and impaired kidney function. Increased angiogenesis and upregulated cytokines were involved. This study is the first to demonstrate a role of SerpinE2 in DN progression by modulating early disease mechanisms.
Exogenous uromodulin and tubular responses in a model of oxalate-induced kidney injury.
de Araújo L, Pina-Lopes N, Costa Silvestre Pereira B … +2 more , Costa-Pessoa JMD, Oliveira-Souza M
Am J Physiol Renal Physiol · 2025 Oct · PMID 40897512 · Publisher ↗
Crystalline nephropathies are associated with kidney injury. Uromodulin (Umod), a glycoprotein produced in the kidneys, regulates salt transport, protecting against urinary tract infections, kidney stones, and kidney inj...
Crystalline nephropathies are associated with kidney injury. Uromodulin (Umod), a glycoprotein produced in the kidneys, regulates salt transport, protecting against urinary tract infections, kidney stones, and kidney injury, contributing to innate immunity. After cleavage by the protease hepsin, Umod is secreted into the tubular lumen. We hypothesize that exogenous Umod may reduce injury associated with crystalline nephropathy. Both in vivo and in vitro models were used. Eight-week-old C57BL/6J male mice were treated with sodium oxalate (NaOx, 9 mg/100 g body wt) and/or Umod (5 µg/animal) and compared with controls. The ST-1 cell line (mouse thick ascending limb of loop of Henle) was treated with calcium oxalate (CaOx; 200 µg/mL) for 6 or 24 h and compared with controls. NaOx treatment caused tubular injury and upregulated proinflammatory and profibrotic factors. Exogenous Umod attenuated NaOx-induced kidney injury. In vitro CaOx treatment decreased Umod expression and induced apoptosis in ST-1 cells, confirmed by elevated caspase-8 immunostaining, whereas Umod reduced the apoptotic response. This study demonstrates that Umod cotreatment attenuated several aspects of NaOx-induced kidney injury. These findings suggest that the multifunctional nature of Umod may have clinical relevance and support the potential utility of urinary Umod as a biomarker of kidney health. This study sheds light on the potential role of exogenous uromodulin in modulating tubular responses to oxalate-induced kidney injury. By exploring its influence on epithelial stress, inflammation, and protein trafficking, these findings provide a more comprehensive understanding of uromodulin's function beyond its known structural and antimicrobial properties. These insights may inform future strategies for preserving tubular integrity in crystal-related renal disorders.
The nuclear export inhibitor selinexor improves kidney function in a rat model of focal segmental glomerulosclerosis.
Gao Y, Hamed M, Martin IV … +12 more , Raffetseder U, Liu X, Leitz A, Moeller MJ, Stamellou E, Jühlen R, Schulz A, Kreutz R, Floege J, Kramann R, Antonin W, Ostendorf T
Am J Physiol Renal Physiol · 2025 Oct · PMID 40897473 · Publisher ↗
Focal segmental glomerulosclerosis (FSGS) is a common glomerular pathology characterized by podocyte injury, which can lead to kidney failure. Among the factors contributing to podocyte damage are mutations in nuclear po...
Focal segmental glomerulosclerosis (FSGS) is a common glomerular pathology characterized by podocyte injury, which can lead to kidney failure. Among the factors contributing to podocyte damage are mutations in nuclear pore complexes (NPCs), which regulate nuclear-cytoplasmic transport of proteins and RNAs. Defective NPCs can accumulate in highly differentiated, nondividing cells such as podocytes. However, their role in podocyte dysfunction is largely unexplored, particularly as a potential therapeutic target. To address this, we investigated the effects of selinexor (KPT-330), a drug that inhibits XPO1-mediated nuclear-cytoplasmic protein export. In HeLa cells, KPT-330 restored compromised NPC function. Munich Wistar Fröemter (MWF) rats, a model for spontaneous FSGS development, aged 10 wk, were treated with KPT-330 for 10 wk and then observed for another 20 wk. Improvements in kidney function were observed at the end of the 10-wk treatment period, with serum creatinine significantly lower in the KPT-330 group (34.11 ± 1.77 μmol/L) versus the vehicle group (39.25 ± 3.54 μmol/L, < 0.01). Serum cystatin C levels remained lower in the KPT-330 group (3.62 ± 0.39 μg/mL) versus vehicle (4.19 ± 0.44 μg/mL, < 0.05) after an additional 20 wk without treatment. Hyperlipidemia was significantly reduced immediately after the end of the 10-wk KPT-330 treatment compared with vehicle (triglyceride: 1.23 ± 0.34 mmol/L vs. 1.92 ± 0.4 mmol/L, < 0.01; total cholesterol: 1.47 ± 0.08 mmol/L vs. 2.96 ± 0.44 mmol/L, < 0.0001). However, histopathological parameters, including glomerulosclerosis, podocyte numbers, and activation of parietal epithelial cells, showed that kidney damage continued to progress. Thus, KPT-330 has beneficial effects on kidney function, but was not sufficient to halt the histological progression of glomerular damage. Focal segmental glomerulosclerosis (FSGS) involves podocyte injury, potentially linked to dysfunctional nuclear pore complexes (NPCs). We show that selinexor (KPT-330), a nuclear export inhibitor, restores NPC function in vitro. In an FSGS rat model, selinexor improves kidney function, lowers serum creatinine and cystatin C levels, and reduces serum lipid levels. However, histological damage persists, indicating partial but not complete protection. These findings highlight NPC-targeted therapies as a potential strategy for treating FSGS.
The organelle-tethering protein PDZD8 regulates endolysosomal maturation and TLR9-NF-κB signaling in cisplatin-induced acute kidney injury.
Takenaka Y, Maekawa H, Hong YA … +9 more , Sakashita M, Li Q, Kitayama C, Nakamura K, Saipidin M, Shang J, Hirabayashi Y, Nangaku M, Inagi R
Am J Physiol Renal Physiol · 2025 Oct · PMID 40897465 · Publisher ↗
Acute kidney injury (AKI) is a life-threatening condition with high morbidity and mortality, characterized by inflammation linked to organelle stress. Despite its clinical significance, effective therapies remain limited...
Acute kidney injury (AKI) is a life-threatening condition with high morbidity and mortality, characterized by inflammation linked to organelle stress. Despite its clinical significance, effective therapies remain limited. Although organelle dysfunction is recognized as a driver of inflammation in AKI, the role of interorganelle communication in this process remains poorly understood. PDZ domain-containing 8 (PDZD8), a tethering protein on the endoplasmic reticulum (ER), facilitates ER-endolysosome contact that is essential for endolysosomal maturation. The mature endolysosome is a prerequisite for activating the DNA-sensing innate immune receptor, Toll-like receptor 9 (TLR9). Here, we investigated the role of PDZD8 in the TLR9-NF-κB pathway during AKI using knockout (KO) mice and in vitro knockdown in human proximal tubular cells (PTCs). KO mice showed reduced severity of cisplatin-induced AKI and reduced activation of the NF-κB pathway. Mechanistically, PDZD8 knockdown in PTCs impaired endolysosomal maturation and acidification. This functional disruption impeded the proper translocation of TLR9 to endolysosomes, thereby inhibiting the signaling cascade leading to NF-κB activation. Notably, PDZD8 knockdown did not alter mitochondrial morphology or the cytosolic leakage of mitochondrial DNA, an endogenous ligand for TLR9. These findings indicate that PDZD8 is crucial for maintaining endolysosomal homeostasis and regulating the TLR9-NF-κB pathway in cisplatin-induced tubular injury. This study reveals the critical role of PDZD8 in maintaining endolysosomal homeostasis and regulating the TLR9-NF-κB inflammatory pathway in cisplatin-induced acute kidney injury (AKI). Loss of PDZD8 impaired endolysosomal function, suppressing TLR9 activation and downstream inflammation, leading to reduced tubular damage.
Fatty acids and albumin are transported by distinct mechanisms in the proximal tubule.
Garcia NH, Gaivin RJ, Khan S … +5 more , Li V, Rbaibi Y, Weisz OA, Garvin JL, Schelling JR
Am J Physiol Renal Physiol · 2025 Oct · PMID 40875392 · Full text
Under physiologic conditions, proximal tubules depend on basolateral fatty acid (FA) uptake for metabolism. In pathophysiologic conditions due to glomerular filtration barrier disruption, albumin-bound FA undergoes filtr...
Under physiologic conditions, proximal tubules depend on basolateral fatty acid (FA) uptake for metabolism. In pathophysiologic conditions due to glomerular filtration barrier disruption, albumin-bound FA undergoes filtration and proximal tubule reabsorption, which leads to lipotoxicity and tubular atrophy. Apical proximal tubule albumin uptake is accomplished by the megalin/cubilin complex and receptor-mediated endocytosis, whereas apical proximal tubule FA uptake is primarily mediated by apical fatty acid transport protein-2 (FATP2). However, a commonly proposed (but untested) alternative model is that the intact albumin-FA complex is cotransported by megalin/cubilin-mediated endocytosis, similar to apolipoproteins. Microperfused mouse proximal tubules demonstrated divergent one- versus two-phase albumin and FA uptake kinetics, with significantly faster albumin compared with FA uptake. LLC-PK1, human proximal tubule cells (HPCT), and opossum kidney (OK) proximal tubule cell lines all expressed megalin, cubilin, and FATP2 mRNA, though in varying amounts. LLC-PK1 cells showed similar one-phase kinetics of dual fluorescently labeled albumin and FA uptake, whereas HPCT cells demonstrated one-phase albumin and two-phase FA uptake kinetics, with significantly faster albumin compared with FA uptake (similar to perfused proximal tubules). FATP2 inhibition blocked FA uptake, but had no effect on albumin uptake in LLC-PK1 and HPCT cells. Megalin and cubilin deletion in OK cells inhibited albumin uptake, but had no effect on FA uptake. We conclude that apical proximal tubule albumin and FA are transported by distinct mechanisms, implying that FAs dissociate from albumin within the proximal tubule lumen before uptake. Reabsorption of aberrantly filtered albumin-bound fatty acids by the apical proximal tubule is important for chronic kidney disease progression. Whether fatty acids and albumin are taken up as intact complexes or dissociate within the lumen before uptake has been controversial. Data derived from in vitro and ex vivo models demonstrate separate albumin and fatty acid uptake kinetics, implying dissociation before uptake.
KCC3 is not required for the distal convoluted tubule response to reduced dietary potassium intake.
Inoue MK, Yu A, Ferdaus MZ … +10 more , Zhang Y, Su XT, Bock F, Arroyo JP, Cho KY, Ellison DH, Zhang MZ, Harris RC, Delpire E, Terker AS
Am J Physiol Renal Physiol · 2025 Oct · PMID 40875335 · Full text
The distal convoluted tubule (DCT) plays a crucial role in potassium (K) homeostasis, with electrogenic basolateral K flux well established as a regulator of its function. Although the involvement of electroneutral basol...
The distal convoluted tubule (DCT) plays a crucial role in potassium (K) homeostasis, with electrogenic basolateral K flux well established as a regulator of its function. Although the involvement of electroneutral basolateral K transport has been hypothesized, its precise role remains unclear. The electroneutral potassium chloride (Cl) cotransporter, KCC3, is expressed in the kidney, but its role in DCT function has yet to be fully defined. To explore this, we generated a novel animal model with DCT-specific deletion of KCC3. Our results show that KCC3 deletion in DCT cells led to reduced levels of both total and phosphorylated sodium (Na) Cl cotransporter (NCC), along with decreased NCC mRNA expression, indicating a regulatory role for KCC3 in NCC expression at the transcript level. Despite these changes, knockout animals maintained normal electrolyte balance under standard dietary conditions. In response to dietary K restriction, knockout mice showed no significant differences compared with controls-blood K levels, NCC phosphorylation, and with no lysine kinase (WNK) body formation in the DCT remained unchanged. These findings suggest that KCC3 is involved in the basal regulation of NCC expression but is not essential for DCT adaptation to K depletion or for overall K homeostasis. Deletion of KCC3 specifically in distal convoluted tubule cells leads to decreased NCC mRNA transcript abundance as well as a reduction in both total and phosphorylated NCC protein levels. Despite these molecular changes, DCT-specific KCC3 deletion does not disrupt overall potassium homeostasis under either standard or low potassium dietary conditions. These findings suggest that other KCC isoforms, such as KCC4, may be involved in regulating the DCT response to reduced dietary potassium intake.
Role of intestinal claudin-2 in calcium permeability and whole body calcium balance.
Nyimanu D, Behm C, Yu ASL
Am J Physiol Renal Physiol · 2025 Oct · PMID 40857169 · Publisher ↗
Kidney stone disease is characterized by hypercalciuria and intestinal hyperabsorption of calcium, leading to the formation of calcium crystals in the kidney. Claudin-2 is a tight junction protein that forms paracellular...
Kidney stone disease is characterized by hypercalciuria and intestinal hyperabsorption of calcium, leading to the formation of calcium crystals in the kidney. Claudin-2 is a tight junction protein that forms paracellular cation pores, and mutations in its gene are associated with kidney stone disease. We have recently shown that mice deficient in are hypercalciuric due to both decreased renal reabsorption and increased intestinal absorption of calcium and develop medullary mineral deposits reminiscent of kidney stone formers. Therefore, we hypothesized that intestinal claudin-2 is important for calcium secretion and that loss of claudin-2 results in increased net intestinal calcium absorption, thereby contributing to kidney stone disease. To test this, we generated intestine-specific knockout mice using a villin-Cre promoter. Female mice showed deletion only in the intestine; however, male mice showed partial deletion of in kidneys. Ileal and colonic calcium permeability were significantly reduced in knockout animals of both sexes. Knockout animals developed transient hypercalciuria (more severe in males than females) at weaning, which was normalized by 4 wk of age. In metabolic balance studies, there was no change in net calcium absorption and in whole body calcium balance in knockout mice of either sex on normal or high-calcium diet, with the exception that males were in slightly positive calcium balance on normal-calcium diet. Our results show that claudin-2 contributes to intestinal permeability to calcium but does not play a significant role in net intestinal calcium absorption or secretion. Global claudin-2 knockout mice have hypercalciuria due to both intestinal overabsorption of calcium and a renal calcium leak. Here, we generated intestine-specific claudin-2 knockout mice. Ileal and colonic calcium permeability were reduced, but surprisingly these animals exhibited only transient hypercalciuria for 1 wk after weaning. Thus, claudin-2 contributes to intestinal permeability to calcium but does not play a significant role in intestinal calcium absorption or secretion.
MARY1 restores mitochondrial homeostasis and accelerates renal recovery following acute kidney injury.
Santiago Raj PV, Janda J, Scholpa NE … +2 more , Hurtado KA, Schnellmann RG
Am J Physiol Renal Physiol · 2025 Oct · PMID 40857162 · Full text
Acute kidney injury (AKI) is a major clinical concern with limited therapeutic strategies, often leading to chronic kidney disease (CKD) and long-term morbidity. Mitochondrial dysfunction is a major causative factor for...
Acute kidney injury (AKI) is a major clinical concern with limited therapeutic strategies, often leading to chronic kidney disease (CKD) and long-term morbidity. Mitochondrial dysfunction is a major causative factor for AKI onset and progression to CKD. Interventions that restore mitochondrial integrity and cellular energy represent promising therapeutic strategies. This study investigated the potential therapeutic role of MARY1, a novel, potent, and subtype-selective serotonin-2B receptor (5-HTR) antagonist, following ischemia/reperfusion (I/R)-induced AKI in mice and rats. We previously demonstrated that MARY1 induces renal mitochondrial biogenesis (MB), the generation of new functional mitochondria, in vivo. MARY1 (0.3 mg/kg, i.p., daily) administration for 6 days following AKI improves renal function, restores mitochondrial homeostasis and renal vascular integrity, upregulates β-oxidation, and restores genes associated with proximal tubule repair. Moreover, daily treatment with MARY1 for 12 days following AKI restores mitochondrial homeostasis and increases autophagic activity in the renal cortex of mice. These findings establish MARY1-mediated 5-HTR antagonism as a mitochondria-targeted therapeutic strategy that addresses multiple hallmarks of AKI, and as a potential intervention for mitochondrial dysfunction-associated renal diseases. This study identifies MARY1, a subtype selective 5-HT receptor antagonist, as a novel mitochondria-targeted therapeutic for AKI. MARY1 restores mitochondrial homeostasis, enhances renal vascular integrity, and promotes autophagy and β-oxidation following bilateral I/R injury-induced AKI, leading to improved renal recovery in vivo. These findings highlight a novel therapeutic strategy to mitigate AKI progression and mitochondrial dysfunction.
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