{"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><sub>T</sub>), we calculated the paracellular Na<sup>+</sup> over Cl<sup>-</sup> permeability (<i>P</i><sub>Na</sub>/<i>P</i><sub>Cl</sub>) ratio. The <i>P</i><sub>Na</sub>/<i>P</i><sub>Cl</sub> 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><sub>T</sub> 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<sup>-</sup> was K<sup>+</sup> > Rb<sup>+</sup> > Na<sup>+</sup> > Li<sup>+</sup>, 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><sub>Na</sub>/<i>P</i><sub>Cl</sub> 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}
Michael J Spellman, Tala Assaf, Shivani Nangia, Joel Fernandez, Kyle C Nicholson, Blythe D Shepard
{"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514471","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482801","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}
Supaporn Kulthinee, Matthew Warhoover, Luc Puis, L Gabriel Navar, Eman Y Gohar
{"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482798","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}
Niklas Ayasse, Peder Berg, Mads V Sørensen, Samuel L Svendsen, Alan M Weinstein, Jens Leipziger
{"title":"Revisiting voltage-coupled H<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> via the epithelial Na<sup>+</sup> channel (ENaC) enhances electrogenic H<sup>+</sup> secretion via V-type H<sup>+</sup>-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<sup>+</sup> secretion in the collecting duct often appears poorly applicable for rationalizing changes in H<sup>+</sup> 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}
Wei He, Nick Slavik, Jacob Braun, Farshad Samadifam, James A Hokanson
{"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}
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
{"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<sup>+</sup>) and potassium (K<sup>+</sup>) 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> concentrations in 5/6Nx rats, which were accompanied by corresponding increases in plasma aldosterone. Acute K<sup>+</sup> 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<sup>+</sup> load decreased the Na<sup>+</sup>/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<sup>+</sup> 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<sup>+</sup> load with the development of postprandial hyperkalemia. 5/6 Nephrectomy attenuates K<sup>+</sup>-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}
Mia Jensen, Elena-Sofia Heinl, Anna Federlein, Uwe Schwartz, Lars Lund, Kirsten Madsen, Boye L Jensen, Frank Schweda
{"title":"Identification of natriuretic peptide receptor A-related gene expression signatures in podocytes in vivo reveals baseline control of protective pathways.","authors":"Mia Jensen, Elena-Sofia Heinl, Anna Federlein, Uwe Schwartz, Lars Lund, Kirsten Madsen, Boye L Jensen, Frank Schweda","doi":"10.1152/ajprenal.00394.2023","DOIUrl":"10.1152/ajprenal.00394.2023","url":null,"abstract":"<p><p>Natriuretic peptide receptor-A (NPR-A) is the principal receptor for the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Targeted deletion of NPR-A in mouse glomerular podocytes significantly enhances renal injury in vivo in the DOCA-salt experimental model. It was therefore hypothesized that natriuretic peptides exert a direct protective effect on glomerular barrier integrity through activation of NPR-A and modulation of gene expression patterns in podocytes. Green fluorescence-positive podocytes from mice with a conditional deletion of <i>Npr1</i> encoding NPR-A were isolated by fluorescence-activated cell sorting (FACS). Differentially expressed genes (DEGs) in podocytes were identified by RNA sequencing of podocytes from wild-type and NPR-A-deleted mice. Enrichment analysis was performed on the DEGs using Gene Ontology (GO) terms. Identified transcripts were validated by real-time PCR and ELISA of cultured isolated human and mouse glomeruli. In addition, the effect of natriuretic peptides on podocyte migration was investigated by measuring the outgrowth of podocytes from cultured glomeruli. A total of 158 DEGs were identified with 81 downregulated DEGs and 77 upregulated DEGs in <i>Npr1</i>-deficient podocytes. Among the downregulated genes were protein S and semaphorin 3G, which are known to have protective effects in podocytes. Protein S was also expressed in and secreted from isolated human glomeruli. GO enrichment analysis revealed that the upregulated DEGs in NPR-A deficient podocytes were associated with cell migration and motility. In line, BNP significantly decreased podocyte outgrowth from cultured glomeruli. In conclusion, endogenous levels of natriuretic peptides in mice support baseline protective pathways at glomerular podocytes such as protein S and suppress podocyte migration.<b>NEW & NOTEWORTHY</b> A combination of fluorescence-activated cell sorting and RNA sequencing identified 158 changed gene products in adult mouse kidneys with and without podocyte-specific deletion of the natriuretic peptide receptor A. Downregulated products included protein S and semaphorin 3G, both with proven renoprotective impact, whereas upregulated products were related to mobility of podocytes. Protein S was produced and released from human and murine isolated glomeruli, and atrial natriuretic peptide (ANP) led to decreased migration of podocytes.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F806-F821"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303165","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":"Anatomic and functional evidence for renal autonomic innervation in normotensive and hypertensive rats.","authors":"Min Dai, Cai-Yu Li, Jing-Xiao Wang, Xiao-Yu Xu, Shi-Xiu Sun, Ying Kang, Ai-Dong Chen, Ying Han, Guo-Qing Zhu","doi":"10.1152/ajprenal.00133.2024","DOIUrl":"10.1152/ajprenal.00133.2024","url":null,"abstract":"<p><p>Renal denervation (RDN) has been used for treating resistant hypertension. A few recent studies have shown vagal innervation of kidneys causing confusion. This study aimed to provide anatomical and functional evidence for renal autonomic innervation. Experiments were performed in male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Pseudorabies virus (PRV) in the paraventricular nucleus and rostral ventrolateral medulla was prevented by bilateral RDN, but not subdiaphragmatic vagotomy. PRV did not appear in the dorsal motor nucleus of the vagus and nucleus tractus solitarii 72 h after renal injection of PRV. Adrenergic fibers were approximately seven times more than cholinergic fibers in the main renal artery (MRA) and its first (1RA) and second grade (2RA) branches. Adrenergic fibers in 1RA were more than those in MRA and 2RA. Tyrosine hydroxylase immunoreactivity in these arteries was higher in SHR than in WKY. Norepinephrine (NE) increased and α-receptor antagonist reduced vascular ring tension of renal arteries. The effect of NE was greater in 1RA and 2RA than in MRA, which was prevented by α-receptor antagonist. Acetylcholine (ACh) or blockage of β-receptors, M receptors, or N receptors had no significant effects on vascular ring tension and the effect of NE. Renal blood flow was reduced by electrical stimulation of renal nerves but not affected by stimulation of the subdiaphragmatic vagus. These results provide anatomical and functional evidence that kidneys are innervated and renal blood flow is regulated by renal sympathetic nerves rather than the vagus. Renal vasoconstriction is regulated by NE and adrenergic fibers rather than ACh or cholinergic fibers in WKY and SHR.<b>NEW & NOTEWORTHY</b> Kidneys are innervated by renal nerves rather than the vagus. Adrenergic fibers in renal arteries are about seven times more than cholinergic fibers. Renal vasoconstriction is regulated by norepinephrine and adrenergic fibers rather than acetylcholine or cholinergic fibers. Renal blood flow is regulated by renal sympathetic nerves and is not affected by the vagus. These findings provide anatomical and functional evidence for renal autonomic innervation in normotensive and hypertensive rats.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F885-F898"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303163","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}
Gelare Ghajar-Rahimi, Daria Barwinska, Grace E Whipple, Malgorzata M Kamocka, Shehnaz Khan, Seth Winfree, Jennifer Lafontaine, Reham H Soliman, Arin L Melkonian, Anna A Zmijewska, Matthew D Cheung, Amie M Traylor, Yanlin Jiang, Zhengqin Yang, Subhashini Bolisetty, Abolfazl Zarjou, Timmy Lee, James F George, Tarek M El-Achkar, Anupam Agarwal
{"title":"Acute kidney injury results in long-term alterations of kidney lymphatics in mice.","authors":"Gelare Ghajar-Rahimi, Daria Barwinska, Grace E Whipple, Malgorzata M Kamocka, Shehnaz Khan, Seth Winfree, Jennifer Lafontaine, Reham H Soliman, Arin L Melkonian, Anna A Zmijewska, Matthew D Cheung, Amie M Traylor, Yanlin Jiang, Zhengqin Yang, Subhashini Bolisetty, Abolfazl Zarjou, Timmy Lee, James F George, Tarek M El-Achkar, Anupam Agarwal","doi":"10.1152/ajprenal.00120.2024","DOIUrl":"10.1152/ajprenal.00120.2024","url":null,"abstract":"<p><p>The long-term effects of a single episode of acute kidney injury (AKI) induced by bilateral ischemia-reperfusion injury (BIRI) on kidney lymphatic dynamics are not known. The purpose of this study was to determine if alterations in kidney lymphatics are sustained in the long term and how they relate to inflammation and injury. Mice underwent BIRI as a model of AKI and were followed up to 9 mo. Although kidney function markers normalized following initial injury, histological analysis revealed sustained tissue damage and inflammation for up to 9 mo. Transcriptional analysis showed both acute and late-stage lymphangiogenesis, supported by increased expression of lymphatic markers, with unique signatures at each phase. Expression of <i>Ccl21a</i> was distinctly upregulated during late-stage lymphangiogenesis. Three-dimensional tissue cytometry confirmed increased lymphatic vessel abundance, particularly in the renal cortex, at early and late timepoints postinjury. In addition, the study identified the formation of tertiary lymphoid structures composed of CCR7<sup>+</sup> lymphocytes and observed changes in immune cell composition over time, suggesting a complex and dynamic response to AKI involving tissue remodeling and immune cell involvement. This study provides new insights into the role of lymphatics in the progression of AKI to chronic kidney disease.<b>NEW & NOTEWORTHY</b> Here, we perform the first, comprehensive study of long-term lymphatic dynamics following a single acute kidney injury (AKI) event. Using improved three-dimensional image analysis and an expanded panel of transcriptional markers, we identify multiple stages of lymphatic responses with distinct transcriptional signatures, associations with the immune microenvironment, and collagen deposition. This research advances kidney lymphatic biology, emphasizing the significance of longitudinal studies in understanding AKI and the transition to chronic kidney disease.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F869-F884"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334169","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}