American journal of physiology. Renal physiology最新文献

{"title":"The FSGS protein actinin-4 interacts with NKCC2 to regulate thick ascending limb NaCl reabsorption.","authors":"Dipak Maskey, Tang-Dong Liao, D'Anna L Potter, Pablo A Ortiz","doi":"10.1152/ajprenal.00119.2024","DOIUrl":"10.1152/ajprenal.00119.2024","url":null,"abstract":"<p><p>In the kidney, the thick ascending limb (TAL) of the loop of Henle plays a vital role in NaCl homeostasis and blood pressure regulation. In human and animal models of salt-sensitive hypertension, NaCl reabsorption via the apical Na⁺/K⁺/2Cl^- cotransporter (NKCC2) is abnormally increased in the TAL. We showed that NaCl reabsorption is controlled by the presence of NKCC2 at the apical surface of TALs. However, the molecular mechanisms that maintain the steady-state levels of NKCC2 at the apical surface are not clearly understood. Here, we report that NKCC2 interacts with the F-actin cross-linking protein actinin-4 (ACTN4). We find that ACTN4 is expressed in TALs by Western blot and immunofluorescence microscopy. ACTN4 immunoprecipitated with NKCC2 and recombinant glutathione-<i>S</i>-transferase (GST)-ACTN4 pulled down NKCC2 from TAL lysates. ACTN4 is involved in endocytosis in other cells. Therefore, we hypothesized that ACTN4 binds apical NKCC2 and regulates its trafficking. To study the role of ACTN4 in NKCC2 surface expression, we silenced ACTN4 in vivo via shRNA or CRISPR/Cas9 system to decrease ACTN4 expression in TALs. We observed that silencing ACTN4 in vivo via shRNA or CRISPR/Cas9 system increased the amount of NKCC2 at the apical surface of TALs. Consistent with an increase in surface NKCC2, bumetanide-induced diuresis and natriuresis were enhanced by 35% after silencing of ACTN4 in vivo (AV-NKCC2-Cas9: 3,841 ± 709 vs. AAV-gRNA-ACTN4: 5,546 ± 622 µmol Na/8 h, <i>n</i> = 5, <i>P</i> < 0.05). We conclude that ACTN4 binds NKCC2 to regulate its surface expression. Selective depletion of ACTN4 in TALs using shRNA or CRISPR/Cas9 enhances surface NKCC2 and TAL-NaCl reabsorption, indicating that regulation of the ACTN4-NKCC2 interaction is important for renal NaCl reabsorption and could be related to hypertension.<b>NEW & NOTEWORTHY</b> ACTN4 function and dysfunction in glomerular podocytes have been extensively studied. However, the function of ACTN4 in the nephron has not been studied. Our paper shows for the first time that ACTN4, in the nephron, regulates NaCl reabsorption in part by affecting NKCC2 surface expression. Protein-protein interactions between ACTN4 and NKCC2 seem to mediate NKCC2 endocytosis in TALs. When ACTN4 was silenced in the TAL in vivo using CRISPR/Cas9 or shRNAs, surface NKCC2 and NaCl reabsorption increased.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1026-F1036"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514474","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":"Chronic central nervous system leptin administration attenuates kidney dysfunction and injury in a model of ischemia/reperfusion-induced acute kidney injury.","authors":"Jussara M do Carmo, John E Hall, Luzia N S Furukawa, Viktoria Woronik, Xuemei Dai, Emily Ladnier, Zhen Wang, Ana C M Omoto, Alan Mouton, Xuan Li, Emilio M Luna-Suarez, Alexandre A da Silva","doi":"10.1152/ajprenal.00158.2024","DOIUrl":"10.1152/ajprenal.00158.2024","url":null,"abstract":"<p><p>In the present study, we examined whether chronic intracerebroventricular (ICV) leptin administration protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Twelve-week-old male rats were implanted with an ICV cannula into the right lateral ventricle, and 8-10 days after surgery, leptin (0.021 µg/h, <i>n</i> = 8) or saline vehicle (0.5 µL/h, <i>n</i> = 8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On <i>day 8</i> of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle-treated group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (fourth day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. UIR-Leptin-treated rats showed reduced right and left kidney weights (right: 1,040 ± 24 vs. 1,281 ± 36 mg; left: 1,127 ± 71 vs. 1,707 ± 45 mg, for UIR-Leptin and UIR-PF, respectively). ICV leptin infusion improved GFR (0.50 ± 0.06 vs. 0.13 ± 0.03 mL/min/g kidney wt) and reduced kidney injury scores. ICV leptin treatment also attenuated the reduction in circulating adiponectin levels that was observed in UIR-PF rats and increased the circulating white blood cells count compared with UIR-PF rats (16.3 ± 1.3 vs. 9.8 ± 0.6 k/µL). Therefore, we show that leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and injury in a model of ischemia/reperfusion-induced AKI.<b>NEW & NOTEWORTHY</b> A major new finding of this study is that chronic activation of leptin receptors in the CNS markedly attenuates acute kidney injury and protects against severe renal dysfunction after ischemia/reperfusion, independently of leptin's anorexic effects.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F957-F966"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373700","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":"Matrix metalloproteinases in kidney homeostasis and diseases: an update.","authors":"Roderick J Tan, Youhua Liu","doi":"10.1152/ajprenal.00179.2024","DOIUrl":"10.1152/ajprenal.00179.2024","url":null,"abstract":"<p><p>Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease, and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F967-F984"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373702","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":"Axial heterogeneity of superficial proximal tubule paracellular transport in mice.","authors":"Shigeaki Muto, Kazumasa Moriwaki, Daisuke Nagata, Mikio Furuse","doi":"10.1152/ajprenal.00187.2024","DOIUrl":"10.1152/ajprenal.00187.2024","url":null,"abstract":"<p><p>A considerable amount of NaCl reabsorption in proximal tubules (PTs) occurs via the paracellular transport regulated by the tight junction proteins claudins (Cldns). However, the paracellular transport properties in mouse superficial PTs remain unclear. We characterized these properties in superficial PT S1-S3 segments from mice expressing [wild-type (WT, WTS1-WTS3)] or lacking [knockout (KO, KOS1-KOS3)] claudin-2. We isolated and perfused segments with symmetrical solutions in the presence of bath ouabain and measured the diffusion potential upon changing the salt composition of the lumen or bath. Based on the diffusion potential corrected for the liquid junction potential (d<i>V</i>_T), we calculated the paracellular Na⁺ over Cl^- permeability (<i>P</i>_Na/<i>P</i>_Cl) ratio. The <i>P</i>_Na/<i>P</i>_Cl values upon reducing luminal NaCl averaged 1.27, 1.04, and 0.85 in WTS1, WTS2, and WTS3 and 0.34, 0.55, and 0.80 in KOS1, KOS2, and KOS3, respectively. The d<i>V</i>_T values exhibited a symmetrical response to bidirectional NaCl concentration gradients in WTS1-WTS3 and KOS1-KOS3. WTS1 and WTS3 were monovalent cation-selective, with WTS1 demonstrating stronger cation selectivity. The order of permeabilities relative to Cl^- was K⁺ > Rb⁺ > Na⁺ > Li⁺, whereas both KOS1 and KOS3 exhibited monovalent cation selectivity loss and, consequently, enhanced anion selectivity, especially in KOS1. Protamine addition to the lumen and bath similarly decreased <i>P</i>_Na/<i>P</i>_Cl values upon reduced luminal NaCl in the order of WTS1 > WTS3 > KOS3 > KOS1. Therefore, this study presents evidence of axial heterogeneity in paracellular transport across superficial PTs in mice.<b>NEW & NOTEWORTHY</b> Research on isolated perfused S2 segments of proximal tubules in mice, both expressing and lacking claudin-2, indicates that claudin-2 forms leaky monovalent cation-selective paracellular channels within the tight junctions of proximal tubules. This study characterized the paracellular transport properties in isolated and perfused superficial proximal tubule S1-S3 segments in both groups of mice. The findings demonstrate, for the first time, functional heterogeneity in the paracellular pathway along the axis of the superficial proximal tubules.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1067-F1078"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549488","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":"Handling the sugar rush: the role of the renal proximal tubule.","authors":"Michael J Spellman, Tala Assaf, Shivani Nangia, Joel Fernandez, Kyle C Nicholson, Blythe D Shepard","doi":"10.1152/ajprenal.00265.2024","DOIUrl":"10.1152/ajprenal.00265.2024","url":null,"abstract":"<p><p>Blood glucose homeostasis is critical to ensure the proper functioning of the human body. Through the processes of filtration, reabsorption, secretion, and metabolism, much of this task falls to the kidneys. With a rise in glucose and other added sugars, there is an increased burden on this organ, mainly the proximal tubule, which is responsible for all glucose reabsorption. In this review, we focus on the current physiological and cell biological functions of the renal proximal tubule as it works to reabsorb and metabolize glucose and fructose. We also highlight the physiological adaptations that occur within the proximal tubule as sugar levels rise under pathophysiological conditions including diabetes. This includes the detrimental impacts of an excess glucose load that leads to glucotoxicity. Finally, we explore some of the emerging therapeutics that modulate renal glucose handling and the systemic protection that can be realized by targeting the reabsorptive properties of the kidney.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1013-F1025"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514471","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":"Cardiac surgery-associated acute kidney injury in cardiopulmonary bypass: a focus on sex differences and preventive strategies.","authors":"Supaporn Kulthinee, Matthew Warhoover, Luc Puis, L Gabriel Navar, Eman Y Gohar","doi":"10.1152/ajprenal.00106.2024","DOIUrl":"10.1152/ajprenal.00106.2024","url":null,"abstract":"<p><p>Cardiac surgery-associated acute kidney injury (CSA-AKI) is a high-risk complication with well-recognized increased morbidity and mortality after cardiac surgery attributable in large part to cardiopulmonary bypass (CPB)-associated factors contributing to AKI including hemodilution, hypothermia, hypotension, and exposure to artificial surfaces. These conditions disrupt the renal microcirculation and activate local and systemic inflammatory responses to nonpulsatile flow and low perfusion pressure. The underlying mechanisms of CSA-AKI in CPB are not fully understood, and the incidence of CSA-AKI remains high at around 30%. Furthermore, women appear to be more vulnerable than men to the renal injury associated with CPB even though the overall incidence of cardiovascular and kidney diseases is lower in premenopausal women. Nevertheless, estrogen elicits renoprotective effects in several ways including mitigating inflammation, promoting natriuresis, and endothelial protection as shown in preclinical studies. However, women have higher rates of CSA-AKI and these are exacerbated in postmenopausal women. This leads to the conundrum of whether sex, age, and hormonal status differences influence CSA-AKI. In this review, we briefly discuss the pathophysiology of CSA-AKI in CPB and sex differences in kidney functions with a focus on the possible role of estrogen-specific effects in CPB and also possible differences in CPB in women including greater hemodilution. Furthermore, we review strategies to prevent CSA-AKI in CPB with a highlight for potential sex-specific strategies. Improving our understanding of the impact of sex and sex hormones on CSA-AKI initiation and development will allow us to better manage the CPB strategies delivered to all patients.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F994-F1004"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482798","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":"Maternal malnutrition in mice impairs nephrogenesis by disrupting DNA methylation of regulatory regions.","authors":"Yaniv Makayes, Eden Abergel, Athar Amleh, Dan Binyamin Varshavsky, Rimma Fok, Batia Azria, Ihab Ansari, Yehudit Bergman, Morris Nechama, Oded Volovelsky","doi":"10.1152/ajprenal.00169.2024","DOIUrl":"10.1152/ajprenal.00169.2024","url":null,"abstract":"<p><p>Maternal caloric restriction during pregnancy significantly impacts kidney development, influencing susceptibility to chronic kidney disease in adulthood. This study explores DNA methylation changes in nephron progenitor cells resulting from caloric restriction and their implications for kidney health. Global DNA hypomethylation is observed in nephron progenitors from caloric-restricted embryos, with specific genomic regions displaying distinct methylation patterns, including hypomethylation and hypermethylation. Differentially methylated regions exhibit enhanced chromatin accessibility, indicating biological relevance. Hypomethylated regions are enriched for genes associated with developmental processes, reflecting changes in gene expression and highlighting their functional relevance in kidney development. The study also reveals that supplementing methionine, an essential amino acid, restores disrupted DNA methylation patterns, particularly in enhancer regions, emphasizing methionine's critical role in regulating nephron progenitor cell epigenetics and ensuring proper kidney development. The intricate relationship between maternal nutrition, dynamic DNA methylation, and kidney development is highlighted, emphasizing the enduring impact of early-life nutritional challenges on kidney function. This research elucidates epigenetic mechanisms as mediators for the lasting effects of maternal caloric restriction on kidney health. The study contributes valuable insights into the origins of chronic kidney diseases during early developmental stages, offering potential interventions to mitigate adverse outcomes.<b>NEW & NOTEWORTHY</b> Our study establishes a direct link between maternal caloric restriction, DNA methylation patterns in nephron progenitor cells, and kidney development. We reveal consistent alterations in methylation patterns, coupled with corresponding shifts in the expression of genes related to kidney development and cell proliferation. Methionine supplementation emerges as a promising intervention, effectively restoring disrupted DNA methylation patterns. These findings pave the way for potential therapeutics, optimizing kidney development and mitigating the burden of chronic kidney disease in adulthood.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1037-F1048"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482801","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":"Revisiting voltage-coupled H⁺ secretion in the collecting duct.","authors":"Niklas Ayasse, Peder Berg, Mads V Sørensen, Samuel L Svendsen, Alan M Weinstein, Jens Leipziger","doi":"10.1152/ajprenal.00023.2024","DOIUrl":"10.1152/ajprenal.00023.2024","url":null,"abstract":"<p><p>Experimental studies have shown that V-type ATPase-driven H⁺ secretion is dependent on transepithelial voltage. On this basis, the \"voltage hypothesis\" of urinary acidification by the collecting duct was derived. Accordingly, it has been supposed that the lumen-negative potential created by the reabsorption of Na⁺ via the epithelial Na⁺ channel (ENaC) enhances electrogenic H⁺ secretion via V-type H⁺-ATPase. This concept continues to be widely used to explain acid/base disorders. Importantly, however, a solid proof of principle for the voltage hypothesis in physiologically relevant situations has not been reached. Rather, it has been challenged by recent in vivo functional studies. In this review, we outline the arguments and experimental observations explaining why voltage-coupled H⁺ secretion in the collecting duct often appears poorly applicable for rationalizing changes in H⁺ secretion as a function of more or less ENaC function in the collecting duct.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F931-F945"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334172","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":"Faster bladder filling in rats reduces detrusor overactivity but worsens (i.e., decreases) bladder compliance.","authors":"Wei He, Nick Slavik, Jacob Braun, Farshad Samadifam, James A Hokanson","doi":"10.1152/ajprenal.00209.2024","DOIUrl":"10.1152/ajprenal.00209.2024","url":null,"abstract":"<p><p>The impact of bladder filling rate on cystometric outcomes remains unclear. Clinically, faster bladder filling is believed to increase the likelihood of observing detrusor overactivity (DO) in those with bladder dysfunction, although evidence of this is lacking. We executed this study to clarify how changes in bladder filling rate impact cystometric parameters. Urethane-anesthetized female CD rats (<i>n</i> = 19) underwent bladder filling at five different fill rates, a baseline rate scaled to have a filling phase of ∼7 min (in line with our previous work) and scaled rates of 1/3×, 2×, 4×, and 8× that speed. Contrary to expectations, filling at faster rates decreased the likelihood of observing detrusor overactivity, with 4× and 8× filling rates demonstrating less detrusor overactivity than the baseline (1×) rate (<i>P</i> = 0.0091 for 4× and <i>P</i> = 0.019 for 8×). However, faster filling rates did decrease bladder compliance. Filling at 4× and 8× demonstrated decreased bladder compliance compared to 1× (<i>P</i> = 0.032 for 4× and <i>P</i> < 0.0001 for 8×). Finally, increasing the filling rate led to increases in bladder capacity at 4× (<i>P</i> = 0.034) and 8× (<i>P</i> = 0.0066) relative to 1×. These results suggest that, contrary to expectations, faster filling may not be more effective at eliciting detrusor overactivity (i.e., not a better diagnostic approach). As reductions in detrusor overactivity and increases in bladder capacity are critical parameters for evaluating preclinical therapeutics, faster filling may impair the ability to demonstrate further improvements.<b>NEW & NOTEWORTHY</b> Little is known about the effects of different bladder filling rates on cystometric results. Various sources have suggested that faster filling is \"provocative\" to the bladder. However, in this study we varied bladder filling rates in anesthetized rats and observed less detrusor overactivity with faster filling, not more. We explain this discrepancy as a miscommunication about what being provocative means, where faster filling leads to worse bladder compliance (as we observed), not more detrusor overactivity.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F985-F993"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482800","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":"5/6 Nephrectomy impairs acute kaliuretic responses and predisposes to postprandial hyperkalemia.","authors":"Kuang-Yu Wei, Martin Gritter, A H Jan Danser, Liffert Vogt, Martin H de Borst, Joris I Rotmans, Pedro Henrique Imenez Silva, Ewout J Hoorn","doi":"10.1152/ajprenal.00195.2024","DOIUrl":"10.1152/ajprenal.00195.2024","url":null,"abstract":"<p><p>The susceptibility of patients with chronic kidney disease to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na⁺) and potassium (K⁺) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K⁺ loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this with the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K⁺ loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K⁺ concentrations in 5/6Nx rats, which were accompanied by corresponding increases in plasma aldosterone. Acute K⁺ loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase and the sodium-chloride cotransporter both in sham and 5/6Nx rats. In contrast, the acute K⁺ load decreased the Na⁺/hydrogen exchanger 3 and increased serum- and glucocorticoid-regulated kinase 1 and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K⁺ load, which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia.<b>NEW & NOTEWORTHY</b> Rats who underwent 5/6 nephrectomy demonstrate a reduced ability to excrete an acute K⁺ load with the development of postprandial hyperkalemia. 5/6 Nephrectomy attenuates K⁺-induced natriuresis and impairs ENaC regulation despite intact NCC dephosphorylation and increased plasma aldosterone. This offers a potential explanation for why patients with chronic kidney disease are predisposed to postprandial hyperkalemia.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1005-F1012"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482797","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}