American journal of physiology. Renal physiology最新文献

{"title":"Diurnal function and expression of aquaporins in the mouse kidney.","authors":"Hung Nguyen, Nha Van Huynh, Kelly A Hyndman","doi":"10.1152/ajprenal.00162.2025","DOIUrl":"10.1152/ajprenal.00162.2025","url":null,"abstract":"<p><p>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 <i>Aqp</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F601-F614"},"PeriodicalIF":3.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12767696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Underlying metabolic syndrome exacerbates <i>Vibrio vulnificus-</i>induced acute kidney injury via systemic Th17/Treg dysregulation.","authors":"Madhura Pravin More, Punnag Saha, Subhajit Roy, Ayushi Trivedi, Saurabh Chatterjee","doi":"10.1152/ajprenal.00073.2025","DOIUrl":"10.1152/ajprenal.00073.2025","url":null,"abstract":"<p><p>Climate change has led to a rise in <i>Vibrio vulnificus</i> 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 <i>V. vulnificus</i> sepsis-associated AKI. Adult C57BL/6J mice were placed on a standard CHOW diet or a 60% kcal HFD for 6 wk before infection. <i>V. vulnificus</i> infection was induced via intragastric administration by oral gavage of 10⁸ colony-forming units of <i>V. vulnificus</i> 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 + <i>Vibrio vulnificus</i> 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 <i>V. vulnificus</i> 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.<b>NEW & NOTEWORTHY</b> This study reveals that high-fat diet (HFD)-induced metabolic dysfunction exacerbates <i>Vibrio vulnificus</i> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F627-F644"},"PeriodicalIF":3.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of propofol and sevoflurane anesthesia on renal blood flow and oxygenation during major hemorrhage in pigs.","authors":"Robert Frithiof, Micael Taavo, Arash Emami, Stephanie Franzén","doi":"10.1152/ajprenal.00146.2025","DOIUrl":"10.1152/ajprenal.00146.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F581-F588"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of intestinal claudin-2 in calcium permeability and whole body calcium balance.","authors":"Duuamene Nyimanu, Christine Behm, Alan S L Yu","doi":"10.1152/ajprenal.00133.2025","DOIUrl":"10.1152/ajprenal.00133.2025","url":null,"abstract":"<p><p>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 <i>Cldn2</i> 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 <i>Cldn2</i> knockout mice using a villin-Cre promoter. Female mice showed <i>Cldn2</i> deletion only in the intestine; however, male mice showed partial deletion of <i>Cldn2</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F432-F443"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First Author Highlights.","authors":"","doi":"10.1152/ajprenal.2025.329.4.AU","DOIUrl":"https://doi.org/10.1152/ajprenal.2025.329.4.AU","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"329 4","pages":"i-ii"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of nuclear receptors, lipid metabolism, and mitochondrial function in the pathogenesis of diabetic kidney disease.","authors":"Eleni Hughes, Xiaoxin X Wang, Lily Sabol, Keely Barton, Sujit Hegde, Komuraiah Myakala, Ewa Krawczyk, Avi Rosenberg, Moshe Levi","doi":"10.1152/ajprenal.00110.2025","DOIUrl":"10.1152/ajprenal.00110.2025","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and remains a significant clinical challenge due to its complex pathogenesis. This review explores the intricate interplay of metabolic, inflammatory, and cellular mechanisms that drive DKD progression, with a particular focus on lipid metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell injury, and epigenetic modifications. Advances in histopathological and molecular studies have expanded our understanding of glomerular, tubular, and vascular abnormalities in DKD, highlighting the critical role of nuclear hormone receptors, transcription factors, and G protein-coupled receptors in regulating renal lipid accumulation, mitochondrial function, inflammation, oxidative stress, and fibrotic pathways. In addition, emerging evidence implicates novel cell death mechanisms, including ferroptosis, necroptosis, pyroptosis, and PANoptosis, in DKD pathology. Epigenetic modifications, including DNA methylation, histone modifications, and noncoding RNAs, further contribute to disease progression by regulating gene expression in response to metabolic stress. As current therapeutic strategies remain insufficient to prevent DKD progression, this review also discusses novel molecular targets and emerging therapeutic approaches aimed at mitigating lipid toxicity, enhancing mitochondrial function, and suppressing inflammation. By integrating insights from histopathology, molecular biology, and translational research, this review provides a comprehensive framework for developing future strategies to delay or prevent DKD progression.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F510-F547"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The nuclear export inhibitor selinexor improves kidney function in a rat model of focal segmental glomerulosclerosis.","authors":"Yingying Gao, Mohamed Hamed, Ina V Martin, Ute Raffetseder, Xiyang Liu, Anna Leitz, Marcus J Moeller, Eleni Stamellou, Ramona Jühlen, Angela Schulz, Reinhold Kreutz, Jürgen Floege, Rafael Kramann, Wolfram Antonin, Tammo Ostendorf","doi":"10.1152/ajprenal.00143.2025","DOIUrl":"10.1152/ajprenal.00143.2025","url":null,"abstract":"<p><p>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, <i>P</i> < 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, <i>P</i> < 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, <i>P</i> < 0.01; total cholesterol: 1.47 ± 0.08 mmol/L vs. 2.96 ± 0.44 mmol/L, <i>P</i> < 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F496-F509"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of chronic kidney disease on arteriovenous fistula remodeling: studies in a murine model of autosomal dominant polycystic kidney disease.","authors":"Suzanne L Laboyrie, Dorien J M Peters, Roel Bijkerk, Eduard Pierre de Winter, Jacques M G J Duijs, Juliette A de Klerk, Margreet R de Vries, Joris I Rotmans","doi":"10.1152/ajprenal.00354.2024","DOIUrl":"10.1152/ajprenal.00354.2024","url":null,"abstract":"<p><p>The arteriovenous fistula (AVF) is the gold standard for hemodialysis vascular access, although inadequate vascular remodeling and intimal hyperplasia pose a major limitation. It is essential to study this in a clinically relevant model. We used an autosomal dominant polycystic kidney disease (ADPKD) model, the most common hereditary cause of chronic kidney disease (CKD), to study the effect of CKD on AVFs. Jugular-carotid AVFs were created in adult <i>B6OlaPkd1</i>^nl/nl (ADPKD) mice and <i>B6OlaPkd1</i>^+/+ littermates. AVFs were harvested 7 days postsurgery for bulk mRNA sequencing or 3 wk postsurgery for histological analysis. We performed weekly AVF flow measurements using Doppler ultrasound and assessed kidney morphology and function by histology and blood urea analysis. Blood pressure was measured using a tail cuff, before and 6 days after AVF surgery. Longitudinal flow data was analyzed using mixed-effects model, histological data using the Mann-Whitney <i>U</i> test. <i>Pkd1</i>^nl/nl mice developed cystic kidneys and elevated blood urea levels (8.7 ± 2.8 mmol/L vs. 24.0 ± 3.8 mmol/L) and higher mean arterial blood pressure (92 vs. 113). AVF flow in <i>Pkd1</i>^nl/nl mice was consistently higher post-AVF creation (1.9-fold difference, <i>P</i> < 0.001), with a 50% reduction in intimal hyperplasia and 30% increase in luminal AVF volume. RNA sequencing showed altered regulation of extracellular matrix in the venous ADPKD AVF, with reduced collagen deposition in the venous outflow tract. The arterial AVF wall had disruption of the elastic laminae. <i>Pkd1</i>^nl/nl mice are a suitable model to study AVF remodeling in a CKD setting, resulting in enhanced luminal volume and higher AVF flow when compared with normotensive mice with normal kidney function.<b>NEW & NOTEWORTHY</b> This work explores the impact of chronic kidney disease (CKD) on arteriovenous fistula (AVF) remodeling using an autosomal dominant polycystic kidney disease (ADPKD) mouse model. Our findings reveal that ADPKD enhances AVF flow and luminal volume while reducing intimal hyperplasia, due to altered extracellular matrix deposition, offering new insights into the vascular AVF changes in a CKD setting. This study highlights the suitability of the ADPKD model for investigating AVF remodeling in a CKD context.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F453-F464"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SerpinE2 deficiency exacerbates glomerular injury in diabetic nephropathy through dysregulated angiogenesis and inflammatory responses.","authors":"Leila Idir, Junjie Yu, Philippe Bonnin, Benjamin Richard, Stéphane Loyau, Yacine Boulaftali, Marie-Christine Bouton, Véronique Arocas","doi":"10.1152/ajprenal.00193.2025","DOIUrl":"10.1152/ajprenal.00193.2025","url":null,"abstract":"<p><p>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 <i>SerpinE2</i>^-/- 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F548-F556"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MARY1 restores mitochondrial homeostasis and accelerates renal recovery following acute kidney injury.","authors":"Paul Victor Santiago Raj, Jaroslav Janda, Natalie E Scholpa, Kevin A Hurtado, Rick G Schnellmann","doi":"10.1152/ajprenal.00232.2025","DOIUrl":"10.1152/ajprenal.00232.2025","url":null,"abstract":"<p><p>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-HT_2BR) 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-HT_2BR antagonism as a mitochondria-targeted therapeutic strategy that addresses multiple hallmarks of AKI, and as a potential intervention for mitochondrial dysfunction-associated renal diseases.<b>NEW & NOTEWORTHY</b> This study identifies MARY1, a subtype selective 5-HT_2B 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F411-F421"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}