American journal of physiology. Renal physiology最新文献

{"title":"Chronic infusion of the tryptophan metabolite kynurenine increases mean arterial pressure in male Sprague-Dawley rats.","authors":"Debra L Irsik, Jian-Kang Chen, Wendy B Bollag, Carlos M Isales","doi":"10.1152/ajprenal.00019.2024","DOIUrl":"10.1152/ajprenal.00019.2024","url":null,"abstract":"<p><p>Chronic kidney disease is the loss of renal function that can occur from aging or through a myriad of other disease states. Rising serum concentrations of kynurenine, a tryptophan metabolite, have been shown to correlate with increasing severity of chronic kidney disease. This study used chronic intravenous infusion in conscious male Sprague-Dawley rats to test the hypothesis that kynurenine can induce renal damage and promote alterations in blood pressure, heart rate, and decreased renal function. We found that kynurenine infusion increased mean arterial pressure, increased the maximum and minimum range of heart rate, decreased glomerular filtration rate, and induced kidney damage in a dose-dependent manner. This study shows that kynurenine infusion can promote kidney disease in healthy, young rats, implying that the increase in kynurenine levels associated with chronic kidney disease may establish a feed-forward mechanism that exacerbates the loss of renal function.<b>NEW & NOTEWORTHY</b> In humans, an elevated serum concentration of kynurenine has long been associated with negative outcomes in various disease states as well as in aging. However, it has been unknown whether these increased kynurenine levels are mediating the disorders or simply associated with them. This study shows that chronically infusing kynurenine can contribute to the development of hypertension and kidney impairment. The mechanism of this action remains to be determined in future studies.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F199-F207"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261821","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":"Expression and localization of HSD17B13 along mouse urinary tract.","authors":"Haibo Zhang, Jiazhen Chang, Zhihong Dai, Qiuming Wang, Rongfang Qiao, Yingzhi Huang, Beibei Ma, Jiuchao Jiang, Chunhua Zhu, Wen Su, Xiaoyan Zhang, Youfei Guan","doi":"10.1152/ajprenal.00069.2024","DOIUrl":"10.1152/ajprenal.00069.2024","url":null,"abstract":"<p><p>17β-Hydroxysteroid dehydrogenase-13 (HSD17B13), a newly identified lipid droplet-associated protein, plays an important role in the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Emerging evidence demonstrates that NASH is an independent risk factor for chronic kidney disease, which is frequently accompanied by renal lipid accumulation. In addition, the HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven NAFLD. At present, the role of HSD17B13 in lipid accumulation in the kidney is unclear. This study utilized bioinformatic and immunostaining approaches to examine the expression and localization of HSD17B13 along the mouse urinary tract. We found that HSD17B13 is constitutively expressed in the kidney, ureter, and urinary bladder. Our findings reveal for the first time, to our knowledge, the precise localization of HSD17B13 in the mouse urinary system, providing a basis for further studying the pathogenesis of HSD17B13 in various renal and urological diseases.<b>NEW & NOTEWORTHY</b> HSD17B13, a lipid droplet-associated protein, is crucial in nonalcoholic fatty liver disease (NAFLD) development. NAFLD also independently raises chronic kidney disease (CKD) risk, often with renal lipid buildup. However, HSD17B13's role in CKD-related lipid accumulation is unclear. This study makes the first effort to examine HSD17B13 expression and localization along the urinary system, providing a basis for exploring its physiological and pathophysiological roles in the kidney and urinary tract.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F146-F157"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081881","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":"Corrigendum for McKinzie et al., volume 326, 2024, p. F644-F660.","authors":"","doi":"10.1152/ajprenal.00417.2023_COR","DOIUrl":"https://doi.org/10.1152/ajprenal.00417.2023_COR","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"327 1","pages":"F198"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536147","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":"<i>Kcnma1</i> alternative splicing in mouse kidney: regulation during development and by dietary K⁺ intake.","authors":"Sarah Christine M Whelan, Stephanie M Mutchler, Agnes Han, Catherine Priestley, Lisa M Satlin, Thomas R Kleyman, Shujie Shi","doi":"10.1152/ajprenal.00100.2024","DOIUrl":"10.1152/ajprenal.00100.2024","url":null,"abstract":"<p><p>The pore-forming α-subunit of the large-conductance K⁺ (BK) channel is encoded by a single gene, <i>KCNMA1.</i> BK channel-mediated K⁺ secretion in the kidney is crucial for overall renal K⁺ homeostasis in both physiological and pathological conditions. BK channels achieve phenotypic diversity by various mechanisms, including substantial exon rearrangements at seven major alternative splicing sites. However, <i>KCNMA1</i> alternative splicing in the kidney has not been characterized. The present study aims to identify the major splice variants of mouse <i>Kcnma1</i> in whole kidney and distal nephron segments. We designed primers that specifically cross exons within each alternative splice site of mouse <i>Kcnma1</i> and performed real-time quantitative RT-PCR (RT-qPCR) to quantify relative abundance of each splice variant. Our data suggest that <i>Kcnma1</i> splice variants within mouse kidney are less diverse than in the brain. During postnatal kidney development, most <i>Kcnma1</i> splice variants at site 5 and the COOH terminus increase in abundance over time. Within the kidney, the regulation of <i>Kcnma1</i> alternative exon splicing within these two sites by dietary K⁺ loading is both site and sex specific. In microdissected distal tubules, the <i>Kcnma1</i> alternative splicing profile, as well as its regulation by dietary K⁺, are distinctly different than in the whole kidney, suggesting segment and/or cell type specificity in <i>Kcnma1</i> splicing events. Overall, our data provide evidence that <i>Kcnma1</i> alternative splicing is regulated during postnatal development and may serve as an important adaptive mechanism to dietary K⁺ loading in mouse kidney.<b>NEW & NOTEWORTHY</b> We identified the major <i>Kcnma1</i> splice variants that are specifically expressed in the whole mouse kidney or aldosterone-sensitive distal nephron segments. Our data suggest that <i>Kcnma1</i> alternative splicing is developmentally regulated and subject to changes in dietary K⁺.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F49-F60"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081651","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":"Cilia-deficient renal tubule cells are primed for injury with mitochondrial defects and aberrant tryptophan metabolism.","authors":"Xiaofeng Zuo, Brennan Winkler, Kasey Lerner, Daria V Ilatovskaya, Aleksandra S Zamaro, Yujing Dang, Yanhui Su, Peifeng Deng, Wayne Fitzgibbon, Jessica Hartman, Kwon Moo Park, Joshua H Lipschutz","doi":"10.1152/ajprenal.00225.2023","DOIUrl":"10.1152/ajprenal.00225.2023","url":null,"abstract":"<p><p>The exocyst and Ift88 are necessary for primary ciliogenesis. Overexpression of Exoc5 (OE), a central exocyst component, resulted in longer cilia and enhanced injury recovery. Mitochondria are involved in acute kidney injury (AKI). To investigate cilia and mitochondria, basal respiration and mitochondrial maximal and spare respiratory capacity were measured in Exoc5 OE, Exoc5 knockdown (KD), Exoc5 ciliary targeting sequence mutant (CTS-mut), control Madin-Darby canine kidney (MDCK), Ift88 knockout (KO), and Ift88 rescue cells. In Exoc5 KD, Exoc5 CTS-mut, and Ift88 KO cells, these parameters were decreased. In Exoc5 OE and Ift88 rescue cells they were increased. Reactive oxygen species were higher in Exoc5 KD, Exoc5 CTS-mut, and Ift88 KO cells compared with Exoc5 OE, control, and Ift88 rescue cells. By electron microscopy, mitochondria appeared abnormal in Exoc5 KD, Exoc5 CTS-mut, and Ift88 KO cells. A metabolomics screen of control, Exoc5 KD, Exoc5 CTS-mut, Exoc5 OE, Ift88 KO, and Ift88 rescue cells showed a marked increase in tryptophan levels in Exoc5 CTS-mut (113-fold) and Exoc5 KD (58-fold) compared with control cells. A 21% increase was seen in Ift88 KO compared with rescue cells. In Exoc5 OE compared with control cells, tryptophan was decreased 59%. To determine the effects of ciliary loss on AKI, we generated proximal tubule-specific Exoc5 and Ift88 KO mice. These mice had loss of primary cilia, decreased mitochondrial ATP synthase, and increased tryptophan in proximal tubules with greater injury following ischemia-reperfusion. These data indicate that cilia-deficient renal tubule cells are primed for injury with mitochondrial defects in tryptophan metabolism.<b>NEW & NOTEWORTHY</b> Mitochondria are centrally involved in acute kidney injury (AKI). Here, we show that cilia-deficient renal tubule cells both in vitro in cell culture and in vivo in mice are primed for injury with mitochondrial defects and aberrant tryptophan metabolism. These data suggest therapeutic strategies such as enhancing ciliogenesis or improving mitochondrial function to protect patients at risk for AKI.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F61-F76"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891407","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":"Zn²⁺ improves sepsis-induced acute kidney injury by upregulating SIRT7-mediated Parkin acetylation.","authors":"Jun Guo, Zhenhui Yuan, Rong Wang","doi":"10.1152/ajprenal.00337.2023","DOIUrl":"10.1152/ajprenal.00337.2023","url":null,"abstract":"<p><p>Zn²⁺ levels are reported to be correlated with kidney function. We explored the significance of Zn²⁺ in sepsis-induced acute kidney injury (SI-AKI) through the regulation of sirtuin 7 (SIRT7) activity. The sepsis rat model was established by cecal ligation and perforation (CLP) and intraperitoneally injected with ZnSO₄ or SIRT7 inhibitor 97491 (SIRT7i), with renal tubular injury assessed by hematoxylin and eosin staining. In vitro, human renal tubular epithelial cells (HK-2) were induced with lipopolysaccharide to obtain a renal injury cell model, followed by ZnSO₄ or SIRT7i and autophagy inhibitor (3-methyladenine) treatment. Interleukin (IL)-1β, IL-18, reactive oxygen species (ROS), Parkin acetylation level, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) expression levels were determined. The renal tubule injury, inflammation condition, and pyroptosis-related and autophagy-related protein levels were assessed. The pyroptosis in kidney tissues and autophagosome formation were observed by transmission electron microscopy. Zn²⁺ alleviated renal injury in CLP rats and inhibited pyroptosis and its related protein levels by inhibiting SIRT7 activity in septic rat renal tissues. In vitro, Zn²⁺ increased HK-2 cell viability and reduced KIM-1, NGAL, IL-1β, IL-18, NLRP3 inflammasome, cleaved caspase-1, gasdermin D-N levels, and pyroptotic cell number. Zn²⁺ increased autophagosome number and LC3BII/LC3BI ratio and decreased TOM20, TIM23, P62, and mitochondrial ROS levels. Zn²⁺ increased Parkin acetylation by repressing SIRT7 activity. Inhibiting mitophagy partially averted Zn²⁺-inhibited NLRP3 inflammasome activation and apoptosis in HK-2 cells. Zn²⁺ upregulated Parkin acetylation by repressing SIRT7 activity to promote mitophagy and inhibit NLRP3 inflammasome activation and pyroptosis, thus improving SI-AKI.<b>NEW & NOTEWORTHY</b> Zn²⁺ upregulated Parkin acetylation by repressing sirtuin 7 activity to promote mitophagy and inhibit NLRP3 inflammasome activation and pyroptosis, thus improving sepsis-induced acute kidney injury.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F184-F197"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082317","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":"Amiloride lowers plasma TNF and interleukin-6 but not interleukin-17A in patients with hypertension and type 2 diabetes.","authors":"Sai Sindhu Thangaraj, Christina S Oxlund, Henrik Andersen, Per Svenningsen, Jane Stubbe, Yaseelan Palarasah, Micaella Pereira Da Fonseca, Daniel F J Ketelhuth, Camilla Enggaard, Maria Høj Hansen, Jan Erik Henriksen, Ib Abildgaard Jacobsen, Boye L Jensen","doi":"10.1152/ajprenal.00268.2023","DOIUrl":"10.1152/ajprenal.00268.2023","url":null,"abstract":"<p><p>Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na⁺ channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1β, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: <i>1</i>) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension (<i>n</i> = 69, amiloride 5-10 mg/day for 8 wk) and <i>2</i>) patients with hypertension and type 1 diabetes mellitus (T1DM) (<i>n</i> = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K⁺ increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1β. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages.<b>NEW & NOTEWORTHY</b> ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F37-F48"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081867","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":"Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury.","authors":"Cole S Hudson, Anirban Roy, Qingtian Li, Aniket S Joshi, Taijun Yin, Ashok Kumar, David Sheikh-Hamad, Vincent H Tam","doi":"10.1152/ajprenal.00029.2024","DOIUrl":"10.1152/ajprenal.00029.2024","url":null,"abstract":"<p><p>Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin knockout cells following comparable polymyxin B exposures. Compared with polymyxin B exposure alone, concomitant gelofusine significantly increased cell viability as well as reduced LDH release, polymyxin B uptake, mitochondrial superoxide, and apoptosis. Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. In conclusion, the mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury.<b>NEW & NOTEWORTHY</b> Gelofusine is a gelatinous saline solution with the potential to attenuate polymyxin-associated nephrotoxicity. We demonstrated that the mechanisms of gelofusine renal protection involve reducing polymyxin B uptake by proximal tubule cells, limiting subsequent oxidative stress and apoptosis activation. In addition, gelofusine was more effective at reducing cellular injury than a known antioxidant control, methionine, and a megalin knockout cell line, indicating that gelofusine likely has additional pharmacological properties besides only megalin inhibition.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F137-F145"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082172","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.2024.327.1.AU","DOIUrl":"https://doi.org/10.1152/ajprenal.2024.327.1.AU","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"327 1","pages":"i-iv"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735970","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":"Therapeutic α-1-microglobulin ameliorates kidney ischemia-reperfusion injury.","authors":"Mikhail Burmakin, Peter S Gilmour, Magnus Gram, Nelli Shushakova, Ruben M Sandoval, Bruce A Molitoris, Tobias E Larsson","doi":"10.1152/ajprenal.00067.2024","DOIUrl":"10.1152/ajprenal.00067.2024","url":null,"abstract":"<p><p>α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.<b>NEW & NOTEWORTHY</b> A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F103-F112"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082188","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}