American journal of physiology. Renal physiology最新文献

{"title":"Proteomic analysis of urinary extracellular vesicles from patients with ADTKD-HNF1β identifies roles for cilia-related proteins and serpins.","authors":"Eveline J E M Kahlman, Martijn H van Heugten, Lotte E Tholen, Maartje F A Verploegen, Cornelia G Spruijt, Pascal W T C Jansen, Michiel Vermeulen, Joost G J Hoenderop, Ewout J Hoorn, Tom Nijenhuis, Jeroen H F de Baaij","doi":"10.1152/ajprenal.00167.2024","DOIUrl":"10.1152/ajprenal.00167.2024","url":null,"abstract":"<p><p>Autosomal dominant tubulointerstitial kidney disease-subtype hepatocyte nuclear factor 1β (ADTKD-HNF1β) is caused by pathogenic variants in or deletions of the gene encoding transcription factor HNF1β. Patients with the same mutation have variable renal and extrarenal phenotypes, including renal cysts, diabetes, and electrolyte disturbances. The aim of this exploratory study was to provide insight whether pathophysiological effects in the kidney of patients with ADTKD-HNF1β are visible by analyzing their urinary extracellular vesicle (uEV) proteome. We isolated uEVs collected from patients with ADTKD-HNF1β and included patients with autosomal dominant polycystic kidney disease (ADPKD) and patients with chronic kidney disease (CKD) as controls. Subsequent LC-MS/MS proteomics and differential and pathway enrichment analyses were performed. Transcriptional targets of HNF1β were selected with ChIP sequencing to study changes in protein abundance due to loss of HNF1β, and correlation analyses with clinical features were performed. We found differential enrichment of five proteins, enrichment of pathways involved in cilia and cell-cell adhesion, and depletion of several Serpins in patients with ADTKD-HNF1β and ADPKD, compared with patients with CKD. We identified differential enrichment of nine HNF1β transcriptional targets between patients with ADTKD-HNF1β and patients with CKD, and we demonstrated that Serpin abundance negatively correlated with epidermal growth factor receptor (eGFR) in patients with ADTKD-HNF1β (<i>R</i> = -0.52). The uEV proteome of patients with ADTKD-HNF1β shows an enrichment in proteins involved in renal cysts development, with resemblance to ADPKD. These changes provide new insight into the pathophysiology of ADTKD-HNF1β. Their onset and association with cyst development and kidney function decline warrants further study.<b>NEW & NOTEWORTHY</b> Urinary extracellular vesicles (uEVs) present a new method to study ADTKD-HNF1β pathophysiology in the kidney as an alternative for kidney biopsies. Enrichment of pathways involved cytoskeletal organization and cilia in the uEV proteome of patients with ADTDK-HNF1β compared with CKD, which may indicate the presence of renal cysts. In this, we show that ADTKD-HNF1β more closely resembles ADPKD. Altogether, the uEV proteome captures the biological changes that are caused by pathogenic variants in HNF1β.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F530-F541"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517628","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":"Assays to enhance metabolic phenotyping in the kidney.","authors":"Safaa Hammoud, Justin Kern, Sandip Mukherjee, Andrew J Lutkewitte, Prabhleen Singh, Kate Newberry, Brian N Finck, Leslie S Gewin","doi":"10.1152/ajprenal.00232.2024","DOIUrl":"10.1152/ajprenal.00232.2024","url":null,"abstract":"<p><p>The kidney is highly metabolically active, and injury induces changes in metabolism that can impact repair and fibrosis progression. Changes in the expression of metabolism-related genes and proteins provide valuable data, but functional metabolic assays are critical to confirm changes in metabolic activity. Stable isotope metabolomics is the gold standard, but these involve considerable cost and specialized expertise. Both the Seahorse bioflux assays and substrate oxidation assays in tissues ex vivo are two relatively cost-effective assays for interrogating metabolism. Many institutions have access to Seahorse bioflux analyzers, which can easily and quickly generate data, but guidelines to enhance reproducibility are lacking. We investigate how variables (e.g. primary vs. immortalized cells, time in culture) impact the data generated by Seahorse bioflux analyzers. In addition, we show the utility of ³H-palmitate, a new approach for assessing fatty acid oxidation (FAO) in the kidney, in uninjured and injured kidney cortices. The ³H-palmitate substrate oxidation assays also demonstrate significant sex-dependent and strain-dependent differences in rates of fatty acid oxidation. These data should facilitate metabolic interrogation in the kidney field with enhanced reproducibility.<b>NEW & NOTEWORTHY</b> We show significant metabolic differences between both primary and immortalized cells, and among primary cells with different durations in cell culture. In addition, ³H-palmitate oxidation in tissue ex vivo is described as a method novel to the kidney for assessing the complete oxidation of long-chain fatty acids. This method shows that female mice have significantly increased fatty acid oxidation across two different strains of mice and significant strain-specific effects on metabolism.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F563-F577"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017946","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":"Renal macro- and microcirculatory perturbations in acute kidney injury and chronic kidney disease associated with heart failure and cardiac surgery.","authors":"Anton L Trask-Marino, Bruno Marino, Terase F Lancefield, Emily J See, Clive N May, Lindsea C Booth, Jai Raman, Yugeesh R Lankadeva","doi":"10.1152/ajprenal.00266.2024","DOIUrl":"10.1152/ajprenal.00266.2024","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and elevated central venous pressure. However, our understanding of renal microcirculation in heart failure and CKD remains limited. This is largely due to the lack of noninvasive techniques to assess renal microcirculation in patients. Moreover, there is a lack of clinically relevant animal models of heart failure and CKD to advance our understanding of the timing and magnitude of renal microcirculatory dysfunction. Patients with heart failure and CKD commonly require cardiac surgery with cardiopulmonary bypass (CPB) to improve their prognosis. However, acute kidney injury (AKI) is a frequent unresolved clinical complication in these patients. There is emerging evidence that renal microcirculatory dysfunction, characterized by renal medullary hypoperfusion and hypoxia, plays a critical role in the pathogenesis of cardiac surgery-associated AKI. In this review, we consolidate the preclinical and clinical evidence of renal macro- and microcirculatory perturbations in heart failure and cardiac surgery requiring CPB. We also examine emerging biomarkers and therapies that may improve health outcomes for this vulnerable patient population by targeting the renal microcirculation.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F452-F469"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367035","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":"CRB2 depletion induces YAP signaling and disrupts mechanosensing in podocytes.","authors":"Yingyu Sun, Nils M Kronenberg, Sidharth K Sethi, Surjya N Dash, Maria E Kovalik, Benjamin Sempowski, Shelby Strickland, Rupesh Raina, C John Sperati, Xuefei Tian, Shuta Ishibe, Gentzon Hall, Malte C Gather","doi":"10.1152/ajprenal.00318.2024","DOIUrl":"10.1152/ajprenal.00318.2024","url":null,"abstract":"<p><p>Focal segmental glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e., podocytes). Pathogenic mutations in crumbs homolog-2 (CRB2), encoding the type 1 transmembrane protein crumbs homolog-2, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a two-generation Indian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces yes-associated protein (YAP) activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using elastic resonator interference stress microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. Although the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.<b>NEW & NOTEWORTHY</b> We identified a rare compound heterozygous CRB2 mutation as the cause of familial SRNS/FSGS in a two-generation East Asian kindred. Modeling the effect of the mutation, we show that CRB2 knockdown in podocytes induces YAP transcriptional activity and upregulates YAP-mediated mechanosignaling. Using elastic resonator interference stress microscopy (ERISM), we demonstrate that CRB2 knockdown enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2<i>-</i>deficient podocytes.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F578-F595"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588719","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":"Methylseq, single-nuclei RNAseq, and discovery proteomics identify pathways associated with nephron-deficit CKD in the HSRA rat model.","authors":"Andrew R Milner, Ashley C Johnson, Esinam M Attipoe, Wenjie Wu, Lavanya Challagundla, Michael R Garrett","doi":"10.1152/ajprenal.00258.2024","DOIUrl":"10.1152/ajprenal.00258.2024","url":null,"abstract":"<p><p>Low nephron numbers are associated with an increased risk of developing chronic kidney disease (CKD) and hypertension, which are significant global health problems. To investigate the impact of nephron deficiency, our laboratory developed a novel inbred rat model (HSRA rat). In this model, ∼75% of offspring are born with a single kidney (HSRA-S), compared with two-kidney littermates (HSRA-C). HSRA-S rats show impaired kidney development, resulting in ∼20% fewer nephrons. Our previous data and current findings demonstrate that nephron deficit (failure of one kidney to form and altered development in the remaining kidney) predisposes HSRA-S to CKD late in life (with increased proteinuria by 18 mo of age in HSRA-S = 51 ± 3.4 vs. HSRA-C = 8 ± 1.5 mg/24 h). To understand early molecular mechanisms contributing to the increased predisposition to CKD, Methylseq using reduced representation bisulfite sequencing, single-nuclei (sn)RNAseq, and discovery proteomics were performed in kidneys of 4-wk-old HSRA rats. Methylation analysis revealed a small number of differences, including five differentially methylated cytosines and six differentially methylated regions between groups. The snRNAseq analysis identified differentially expressed genes in most kidney cell types, with several hundred genes dysregulated depending on the analysis method (Seurat vs. DESeq2). Notably, many genes are involved in kidney development. Discovery proteomic analysis identified 366 differentially expressed proteins. A key finding was dysregulation of <i>Deptor</i>/DEPTOR and <i>Amdhd2</i>/AMDHD2 across omics layers, suggesting a potential role in compensatory mechanisms or the genetic basis of altered kidney development. Further understanding of these mechanisms may guide interventions to preserve nephron health and slow kidney disease progression.<b>NEW & NOTEWORTHY</b> The HSRA rat is a novel model of nephron deficiency and provides a unique opportunity to study the association between nephron number and chronic kidney disease (CKD). Previous work characterized the impact of age, hypertension, and diabetes on the development of CKD in HSRA animals. This study examined early changes in epigenetics, cell-type specific transcriptome, and proteomic changes in the kidney that likely predispose the model to CKD with age.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F470-F488"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469936","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":"ASK1 limits kidney glucose reabsorption, growth, and mid-late proximal tubule KIM-1 induction when diabetes and Western diet are combined with SGLT2 inhibition.","authors":"Maria Crespo-Masip, Helen A Goodluck, Young Chul Kim, Yuji Oe, Allie Roach, Sadhana Kanoo, Natalia Lopez, Haiyan Zhang, Shawn S Badal, Volker Vallon","doi":"10.1152/ajprenal.00031.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00031.2025","url":null,"abstract":"<p><p>Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor (ASK1i) that attenuated the decline in creatinine-based eGFR in humans with type 2 diabetes and kidney disease but increased the rate of acute kidney injury. This study explored individual and combined kidney effects of selonsertib and the anti-hyperglycemic SGLT2 inhibitor (SGLT2i) dapagliflozin in Western diet-fed male Akita mice, a murine model of early type 1 diabetes mellitus showing signs of systemic but no kidney inflammation. ASK1i reduced elevated plasma levels of pro inflammatory cytokines/chemokines (IL-6, MCP1/CCL2, KC/CXCL1 and IP-10/CXCL10) without significantly changing hyperglycemia, glomerular hyperfiltration, and albuminuria or affecting the blood glucose and glomerular hyperfiltration-lowering effect of SGLT2i. A potential sign of tubular stress, SGLT2i modestly upregulated kidney cortex transcription of pro-inflammatory and pro-fibrotic genes and distal tubule injury marker Ngal. Adding ASK1i to SGLT2i lowered transcription of many of these genes including Ngal. However, ASK1i enhanced kidney glucose reabsorption independent of SGLT2i, and combined ASK1i+SGLT2i increased kidney weight by 30%. This was associated with and positively correlated with upregulation of tubular stress/injury marker, KIM-1, primarily in mid to late proximal tubule. Combined ASK1i+SGLT2i increased tubular injury score but not signs of kidney inflammation or fibrosis beyond a robust increase in kidney mRNA expression of Il6, Ccl2 (Mcp1) and Timp1, associated with increased plasma IL-6 levels. The data support the hypothesis that house-keeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in mid to late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732623","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":"Prolonged Unilateral Renal Ischemia-Reperfusion as a Model for Acute to Chronic Kidney Injury in Female Mice.","authors":"Kaitlynn Stowers, Valeria Rudman-Melnick, Qing Ma, Prasad Devarajan","doi":"10.1152/ajprenal.00280.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00280.2024","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease (CKD). Recent studies have highlighted notable gender differences in the susceptibility and expression of both AKI and CKD. The mechanisms underlying these differences remain unclear, and there is a lack of reliable models for studying the AKI-CKD transition in females. In this study, we evaluated various ischemia times in the unilateral renal ischemia-reperfusion injury (UIR) model in female mice to establish a model for studying the AKI-CKD transition. UIR was induced in the left kidneys of male and female C57Bl/6 mice. Kidney pathology and key injury markers were examined 28 days post-UIR.Comparable pathological changes were observed in female mice subjected to 50- and 60-minute ischemia, similar to those in male mice subjected to 30-minute UIR. Protein levels of key injury markers, including Vim-1, Krt8, and Acta2, were significantly increased in female mice subjected to 50- and 60-minute UIR, comparable to male mice subjected to 30-minute UIR, 28 days post-injury. Additionally, an increase in mRNA expression of key kidney injury markers <i>Col1a1</i>, <i>Vim-1</i>, <i>FN</i>, and <i>Sox4</i>, along with a decline in <i>Slc34a1</i> expression, was observed in female mice subjected to 50- and 60-minute UIR, similar to male mice subjected to 30-minute UIR, at 28 days post-injury. Our findings suggest that the optimal ischemia time for inducing CKD changes in female mice is 50-60 minutes, compared to much shorter injury times in male mice.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712624","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":"ACE2 Deficiency Protects Against Heme Protein-Induced Acute Kidney Injury.","authors":"Anthony J Croatt, Raman Deep Singh, Joseph P Grande, Allan W Ackerman, Susan Gurley, Michael A Barry, Luis A Juncos, Karl A Nath","doi":"10.1152/ajprenal.00061.2025","DOIUrl":"10.1152/ajprenal.00061.2025","url":null,"abstract":"<p><p>Angiotensin-converting enzyme 2 (ACE2) exerts countervailing effects on the renin-angiotensin aldosterone system. ACE2 also engages the spike protein of SARS-CoV-2. ACE2 protein has been shown recently to avidly bind heme. We examined the pathobiologic relevance of this heme-binding property of ACE2 by employing the glycerol-induced model of heme protein mediated AKI (HP-AKI) which is characterized by increased kidney heme content. We studied the response of ACE2-wildtype (ACE2^+/y) and ACE2-deficient (ACE2^-/y) mice to HP-AKI and quantitated kidney and cellular content of heme under relevant conditions. ACE2-deficient mice, compared with ACE2-wildtype mice, were significantly protected against HP-AKI as reflected by filtration markers, less histologic injury, and less expression of apoptosis and ferroptosis markers. ACE2-deficient mice also evinced lesser kidney heme content and a blunted induction of HO-1. HEK293 ACE2-overexpressing cells, compared with HEK293-native, when exposed to heme, retained higher amounts of heme. In HP-AKI, ACE2 expression and activity were reduced, and myoglobin and heme, administered independently, reduced ACE2 expression in the otherwise intact mouse kidney. Finally, with more severe HP-AKI, the protective effect of ACE2 deficiency was attenuated. We conclude that ACE2 deficiency confers protection against HP-AKI. We suggest that this reflects the recently recognized binding of heme to ACE2, such binding serving to facilitate renal entry of heme, a known nephrotoxin. These findings uncover a novel pathway of heme-dependent acute kidney injury. This is the first demonstration of the biologic relevance of chemical binding of heme by ACE2. Finally, we identify heme proteins and heme as novel determinants of ACE2 expression.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712622","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":"Downloadable Tool for Modeling of Salt, Urea and Water Transport in a Renal Tubule Segment: Application to the DCT.","authors":"Nipun U Jayatissa, Shahzad Sohail, Ray Mejia, Adrián R Murillo-de-Ozores, Shaza Khan, Viswanathan Raghuram, Chung-Lin Chou, Chin-Rang Yang, Mark A Knepper","doi":"10.1152/ajprenal.00285.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00285.2024","url":null,"abstract":"<p><p>We have devised a user-friendly downloadable, standalone application that solves a set of ordinary differential equations describing steady-state mass balance for salt (NaCl), urea and water in a single renal tubule with axial flow. The model was programmed in <i>Python</i> using an explicit ordinary differential equation solver. The standalone version allows users to interact with a GUI to insert parameter values and initiate the calculations. It outputs volume flow rate and solute concentrations as a function of position along the tubule. We illustrate the use of the model to address questions about the roles of the mammalian distal convoluted tubule (DCT) in water balance. The simulations suggest an important role for the DCT as a second diluting segment beyond the cortical thick ascending limb (CTAL), consistent with a critical function in excretion of water loads. Simulation of the effect of thiazide diuretics, which inhibit active salt absorption in the DCT, provides an explanation for the observation that these agents can produce hyponatremia when used clinically. The simulations also indicate that the DCT may transport salt in either direction (in accord with micropuncture findings), depending on the salt concentration in the fluid entering from the CTAL. Salt reabsorption by active transport is balanced by passive salt secretion as the luminal salt concentration approaches an asymptotic 'static head' level. The tool will allow users with no mathematical modeling experience to simulate transport in renal tubules, working toward the goal of expanding the use of mathematical modeling in physiology.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665581","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":"Toward a Full-scale model of renal hemodynamics using a reconstructed vascular tree.","authors":"Peidi Xu, Sune Darkner, Olga Sosnovtseva, Niels-Henrik Holstein-Rathlou","doi":"10.1152/ajprenal.00293.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00293.2024","url":null,"abstract":"<p><p>The kidney's vascular network stands out because (i) the microcirculation not only supplies the tissues with oxygen and nutrients, but also supports glomerular filtration in each nephron, (ii) contains the tubuloglomerular feedback, a mechanism that contributes to renal blood flow autoregulation and is unique to the kidney, and (iii) the topology of the renal arterial network influences signaling along the vessels mediating nephron-nephron interactions. We have developed a full-scale vascular model of the rat kidney based on a reconstructed vascular network combined with a nephron model that includes glomerular filtration, tubular reabsorption, and autoregulation of afferent arteriolar resistances. The model evaluates the steady-state operating conditions of approximately 30,000 nephrons in a rat kidney and the efficiency of autoregulation under normal and pathological conditions. The simulation results show how the regulated afferent arteriolar resistances stabilize blood flow in the reconstructed full-scale renal vascular network. It is concluded that by using a reconstructed renal vascular tree, it is possible to develop a realistic full-scale model of the regulation of renal hemodynamics as a first step towards creating a virtual kidney.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659901","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}