American journal of physiology. Renal physiology最新文献

{"title":"5-hydroxytryptamine 1F receptor loss reduces renal vasculature and prevents lasmiditan-induced recovery following moderate-severe acute kidney injury in mice.","authors":"Austin D Thompson, Kai W McAlister, Natalie E Scholpa, Jaroslav Janda, John Hortareas, Teodora G Georgieva, Rick G Schnellmann","doi":"10.1152/ajprenal.00307.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00307.2025","url":null,"abstract":"<p><p>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 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). Additionally, 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 <i>HTR1F</i> 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 <i>HTR1F</i> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254004","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":"Pregnane X receptor (PXR) increases urine concentration by upregulating hypothalamic arginine vasopressin expression.","authors":"Xiaowan Sun, Ruifen Li, Zhilin Luan, Beibei Ma, Hu Xu, Taotao Luo, Yitong Hu, Wenqian Zhao, Rongfang Qiao, Chunxiu Du, Jiahui Cao, Hui Zhou, Yanlin Guo, Jin Zhong, Yufei Zhang, Bin Yang, Youfei Guan, Xiao-Yan Zhang","doi":"10.1152/ajprenal.00187.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00187.2025","url":null,"abstract":"<p><p>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 (PXR^-/-) mice exhibited impaired urine-concentrating ability, leading to a polyuria phenotype. Additionally, treatment of mice with PCN is significantly upregulated, while 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 EMSA 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 urinary concentrating capacity primarily by up regulating the expression of AVP in the hypothalamus.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240537","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":"Decreased parietal epithelial cell density is linked to podocyte depletion and predictors of kidney disease progression in human kidneys.","authors":"Jenna T Ference-Salo, Christopher L O'Connor, Rajasree Menon, Edgar A Otto, Meghan Dailey, Markus Bitzer, Jeffrey A Beamish","doi":"10.1152/ajprenal.00243.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00243.2025","url":null,"abstract":"<p><p>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 also was 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240526","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":"Inducible <i>Avp</i> Knockout Mouse Line.","authors":"Shaza Khan, Lihe Chen, Chung-Lin Chou, Syed J Khundmiri, Mark A Knepper","doi":"10.1152/ajprenal.00340.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00340.2025","url":null,"abstract":"<p><p>Arginine vasopressin (AVP) is a peptide hormone synthesized in the hypothalamus and secreted by the posterior pituitary. Previous studies toward understanding of AVP physiology relied heavily on Brattleboro rats, which have a spontaneous mutation in the <i>Avp</i> 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 <i>Avp</i>. We used CRISPR/Cas9 to insert loxP sites into the <i>Avp</i> gene. These mice were then bred with mice expressing a tamoxifen-inducible Cre recombinase. The resulting conditional knockout mice (<i>Avp</i>^flx/flxCre⁺) are viable, fertile, and healthy before induction. Administration of tamoxifen in 8-12 week-old mice successfully deleted <i>Avp</i>, 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. Additionally, these mice exhibited substantial decreased expression of 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 <i>Avp</i> 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 <i>Avp</i> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240584","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":"Pannexin channels in the kidney.","authors":"Madison Williams, Brooke O'Donnell, Linda Columbus, Leon Delalio, Uta Erdbrügger, Brant E Isakson","doi":"10.1152/ajprenal.00259.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00259.2025","url":null,"abstract":"<p><p>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 to 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226472","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":"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}