American Journal of Physiology-renal Physiology最新文献

{"title":"Loss of endothelial glucocorticoid receptor accelerates organ fibrosis in <i>db/db</i> mice.","authors":"Swayam Prakash Srivastava, Julie E Goodwin","doi":"10.1152/ajprenal.00105.2023","DOIUrl":"10.1152/ajprenal.00105.2023","url":null,"abstract":"<p><p>Endothelial cells play a key role in maintaining homeostasis and are deranged in many disease processes, including fibrotic conditions. Absence of the endothelial glucocorticoid receptor (GR) has been shown to accelerate diabetic kidney fibrosis in part through upregulation of Wnt signaling. The <i>db/db</i> mouse model is a model of spontaneous type 2 diabetes that has been noted to develop fibrosis in multiple organs over time, including the kidneys. This study aimed to determine the effect of loss of endothelial GR on organ fibrosis in the <i>db/db</i> model. <i>db/db</i> mice lacking endothelial GR showed more severe fibrosis in multiple organs compared with endothelial GR-replete <i>db/db</i> mice. Organ fibrosis could be substantially improved either through administration of a Wnt inhibitor or metformin. IL-6 is a key cytokine driving the fibrosis phenotype and is mechanistically linked to Wnt signaling. The <i>db/db</i> model is an important tool to study the mechanisms of fibrosis and its phenotype in the absence of endothelial GR highlights the synergistic effects of Wnt signaling and inflammation in the pathogenesis or organ fibrosis.<b>NEW & NOTEWORTHY</b> The major finding of this work is that endothelial glucocorticoid receptor-mediated upregulation of Wnt signaling and concurrent hyperinflammation work synergistically to exacerbate organ fibrosis in a genetic mouse model of diabetes. This study adds to our understanding of diabetic renal fibrosis and has important implications for the use of metformin in this condition.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F519-F526"},"PeriodicalIF":4.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10639025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10193460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thirty years of the NaCl cotransporter: from cloning to physiology and structure.","authors":"Gerardo Gamba","doi":"10.1152/ajprenal.00114.2023","DOIUrl":"10.1152/ajprenal.00114.2023","url":null,"abstract":"<p><p>The primary structure of the thiazide-sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this cotransporter, from the winter's flounder urinary bladder, following a functional expression strategy. This review outlines some aspects of how the knowledge about thiazide diuretics and NCC evolved, the history of the cloning process, and the expansion of the SLC12 family of electroneutral cotransporters. The diseases associated with activation or inactivation of NCC are discussed, as well as the molecular model by which the activity of NCC is regulated. The controversies in the field are discussed as well as recent publication of the three-dimensional model of NCC obtained by cryo-electron microscopy, revealing not only the amino acid residues critical for Na⁺ and Cl^- translocation but also the residues critical for polythiazide binding to the transporter, opening the possibility for a new era in thiazide diuretic therapy.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F479-F490"},"PeriodicalIF":3.7,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10639029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10250569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Alström syndrome 1 in the regulation of glomerular hemodynamics.","authors":"Sumit R Monu, D'Anna L Potter, Tang-Dong Liao, Keyona Nicole King, Pablo A Ortiz","doi":"10.1152/ajprenal.00017.2023","DOIUrl":"10.1152/ajprenal.00017.2023","url":null,"abstract":"<p><p>Inactivating mutations in the <i>ALMS1</i> gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However, the role of ALMS1 in renal function and hemodynamics is unclear. We previously found that ALMS1 is expressed in thick ascending limbs, where it binds and decreases Na⁺-K⁺-2Cl^- cotransporter activity. We hypothesized that ALMS1 is expressed in macula densa cells and that its deletion enhances tubuloglomerular feedback (TGF) and reduces glomerular filtration rate (GFR) in rats. To test this, homozygous ALMS1 knockout (KO) and littermate wild-type Dahl salt-sensitive rats were studied. TGF sensitivity was higher in ALMS1 KO rats as measured by in vivo renal micropuncture. Using confocal microscopy, we confirmed immunolabeling of ALMS1 in macula densa cells (nitric oxide synthase 1 positive), supporting a role for ALMS1 in TGF regulation. Baseline glomerular capillary pressure was higher in ALMS1 KO rats, as was mean arterial pressure. Renal interstitial hydrostatic pressure was lower in ALMS1 KO rats, which is linked to increased Na⁺ reabsorption and hypertension. GFR was reduced in ALMS1 KO rats. Seven-week-old ALMS1 KO rats were not proteinuric, but proteinuria was present in 18- to 22-wk-old ALMS1 KO rats. The glomerulosclerosis index was higher in 18-wk-old ALMS1 KO rats. In conclusion, ALMS1 is involved in the control of glomerular hemodynamics in part by enhancing TGF sensitivity, and this may contribute to decreased GFR. Increased TGF sensitivity, enhanced glomerular capillary pressure, and hypertension may lead to glomerular damage in ALMS1 KO rats. These are the first data supporting the role of ALMS1 in TGF and glomerular hemodynamics.<b>NEW & NOTEWORTHY</b> ALMS1 is a novel protein involved in regulating tubuloglomerular feedback (TGF) sensitivity, glomerular capillary pressure, and blood pressure, and its dysfunction may reduce renal function and cause glomerular damage.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F418-F425"},"PeriodicalIF":3.7,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10639022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The unique structural and functional characteristics of glomerular endothelial cell fenestrations and their potential as a therapeutic target in kidney disease.","authors":"Natalie C Finch, Chris R Neal, Gavin I Welsh, Rebecca R Foster, Simon C Satchell","doi":"10.1152/ajprenal.00036.2023","DOIUrl":"10.1152/ajprenal.00036.2023","url":null,"abstract":"<p><p>Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their function in glomerular hydraulic permeability, and their aberration in disease can contribute to loss of glomerular filtration function. This review provides a comprehensive update of current understanding of the regulation and biogenesis of fenestrae. We consider diseases in which GEnC fenestration loss is recognized or may play a role and discuss methods with potential to facilitate the study of these critical structures. Literature is drawn from GEnCs as well as other fenestrated cell types such as liver sinusoidal endothelial cells that most closely parallel GEnCs.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F465-F478"},"PeriodicalIF":4.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10639027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10197171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of sleep on chronobiology of micturition among healthy older adults.","authors":"Shachi Tyagi, Neil M Resnick, Becky D Clarkson, Gehui Zhang, Robert T Krafty, Subashan Perera, Arohan R Subramanya, Daniel J Buysse","doi":"10.1152/ajprenal.00025.2023","DOIUrl":"10.1152/ajprenal.00025.2023","url":null,"abstract":"<p><p>Nocturia (waking to void) is prevalent among older adults. Disruption of the well-described circadian rhythm in urine production with higher nighttime urine output is its most common cause. In young adults, their circadian rhythm is modulated by the 24-h secretory pattern of hormones that regulate salt and water excretion, including antidiuretic hormone (ADH), renin, angiotensin, aldosterone, and atrial natriuretic peptide (ANP). The pattern of hormone secretion is less clear in older adults. We investigated the effect of sleep on the 24-h secretion of these hormones in healthy older adults. Thirteen participants aged ≥65 yr old underwent two 24-h protocols at a clinical research center 6 wk apart. The first used a habitual wake-sleep protocol, and the second used a constant routine protocol that removed the influence of sleep, posture, and diet. To assess hormonal rhythms, plasma was collected at 8:00 am, 12:00 pm, 4:00 pm, and every 30 min from 7:00 pm to 7:00 am. A mixed-effects regression model was used to compare subject-specific and mean trajectories of hormone secretion under the two conditions. ADH, aldosterone, and ANP showed a diurnal rhythm that peaked during sleep in the wake-sleep protocol. These nighttime elevations were significantly attenuated within subjects during the constant routine. We conclude that sleep has a masking effect on circadian rhythm amplitude of ADH, aldosterone, and ANP: the amplitude of each is increased in the presence of sleep and reduced in the absence of sleep. Disrupted sleep could potentially alter nighttime urine output in healthy older adults via this mechanism.<b>NEW & NOTEWORTHY</b> Nocturia (waking to void) is the most common cause of sleep interruption among older adults, and increased nighttime urine production is its primary etiology. We showed that in healthy older adults sleep affects the 24-h secretory rhythm of hormones that regulate salt-water balance, which potentially alters nighttime urine output. Further studies are needed to elucidate the impact of chronic insomnia on the secretory rhythms of these hormones.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F407-F417"},"PeriodicalIF":3.7,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10639023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"Hi, how can i help you?\": embracing artificial intelligence in kidney research.","authors":"Anita T Layton","doi":"10.1152/ajprenal.00177.2023","DOIUrl":"10.1152/ajprenal.00177.2023","url":null,"abstract":"<p><p>In recent years, biology and precision medicine have benefited from major advancements in generating large-scale molecular and biomedical datasets and in analyzing those data using advanced machine learning algorithms. Machine learning applications in kidney physiology and pathophysiology include segmenting kidney structures from imaging data and predicting conditions like acute kidney injury or chronic kidney disease using electronic health records. Despite the potential of machine learning to revolutionize nephrology by providing innovative diagnostic and therapeutic tools, its adoption in kidney research has been slower than in other organ systems. Several factors contribute to this underutilization. The complexity of the kidney as an organ, with intricate physiology and specialized cell populations, makes it challenging to extrapolate bulk omics data to specific processes. In addition, kidney diseases often present with overlapping manifestations and morphological changes, making diagnosis and treatment complex. Moreover, kidney diseases receive less funding compared with other pathologies, leading to lower awareness and limited public-private partnerships. To promote the use of machine learning in kidney research, this review provides an introduction to machine learning and reviews its notable applications in renal research, such as morphological analysis, omics data examination, and disease diagnosis and prognosis. Challenges and limitations associated with data-driven predictive techniques are also discussed. The goal of this review is to raise awareness and encourage the kidney research community to embrace machine learning as a powerful tool that can drive advancements in understanding kidney diseases and improving patient care.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F395-F406"},"PeriodicalIF":4.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of a mitochondrial-targeted ubiquinol on vascular function and exercise capacity in chronic kidney disease: a randomized controlled pilot study.","authors":"Danielle L Kirkman,&nbsp;Joseph M Stock,&nbsp;Ninette Shenouda,&nbsp;Natalie J Bohmke,&nbsp;Youngdeok Kim,&nbsp;Jason Kidd,&nbsp;Raymond R Townsend,&nbsp;David G Edwards","doi":"10.1152/ajprenal.00067.2023","DOIUrl":"10.1152/ajprenal.00067.2023","url":null,"abstract":"<p><p>Mitochondria-derived oxidative stress has been implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (means ± SE, age: 62 ± 3 yr and estimated glomerular filtration rate: 45 ± 3 mL/min/1.73 m²) received 4 wk of 20 mg/day MitoQ (MTQ group) or placebo (PLB). Outcomes assessed at baseline and follow-up included macrovascular function measured by flow-mediated dilation, microvascular function assessed by laser-Doppler flowmetry combined with intradermal microdialysis, aortic hemodynamics assessed by oscillometry, and exercise capacity assessed by cardiopulmonary exercise testing. Compared with PLB, MitoQ improved flow-mediated dilation (baseline vs. follow-up: MTQ, 2.4 ± 0.3% vs. 4.0 ± 0.9%, and PLB, 4.2 ± 1.0% vs. 2.5 ± 1.0%, <i>P</i> = 0.04). MitoQ improved microvascular function (change in cutaneous vascular conductance: MTQ 4.50 ± 2.57% vs. PLB -2.22 ± 2.67%, <i>P</i> = 0.053). Central aortic systolic and pulse pressures were unchanged; however, MitoQ prevented increases in augmentation pressures that were observed in the PLB group (<i>P</i> = 0.026). MitoQ did not affect exercise capacity. In conclusion, this study demonstrates the potential for a MitoQ to improve vascular function in CKD. The findings hold promise for future investigations of mitochondria-targeted therapies in CKD.<b>NEW & NOTEWORTHY</b> In this randomized controlled pilot study, we investigated the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in chronic kidney disease. Our novel findings showed that 4-wk supplementation of MitoQ was well tolerated and improved macrovascular endothelial function, arterial hemodynamics, and microvascular function in patients with stage 3-4 chronic kidney disease. Our mechanistic findings also suggest that MitoQ improved microvascular function in part by reducing the NADPH oxidase contribution to vascular dysfunction.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F448-F456"},"PeriodicalIF":4.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence that methylglyoxal and receptor for advanced glycation end products are implicated in bladder dysfunction of obese diabetic <i>ob</i>/<i>ob</i> mice.","authors":"Akila L Oliveira,&nbsp;Matheus L Medeiros,&nbsp;Ana Carolina Ghezzi,&nbsp;Gabriel Alonso Dos Santos,&nbsp;Glaucia Coelho Mello,&nbsp;Fabiola Z Mónica,&nbsp;Edson Antunes","doi":"10.1152/ajprenal.00089.2023","DOIUrl":"10.1152/ajprenal.00089.2023","url":null,"abstract":"<p><p>Glycolytic overload in diabetes causes large accumulation of the highly reactive dicarbonyl compound methylglyoxal (MGO) and overproduction of advanced glycation end products (AGEs), which interact with their receptors (RAGE), leading to diabetes-associated macrovascular complications. The bladder is an organ that stays most in contact with dicarbonyl species, but little is known about the importance of the MGO-AGEs-RAGE pathway to diabetes-associated bladder dysfunction. Here, we aimed to investigate the role of the MGO-AGEs-RAGE pathway in bladder dysfunction of diabetic male and female <i>ob</i>/<i>ob</i> mice compared with wild-type (WT) lean mice. Diabetic <i>ob</i>/<i>ob</i> mice were treated with the AGE breaker alagebrium (ALT-711, 1 mg/kg) for 8 wk in drinking water. Compared with WT animals, male and female <i>ob</i>/<i>ob</i> mice showed marked hyperglycemia and insulin resistance, whereas fluid intake remained unaltered. Levels of total AGEs, MGO-derived hydroimidazolone 1, and RAGE in bladder tissues, as well as fluorescent AGEs in serum, were significantly elevated in <i>ob</i>/<i>ob</i> mice of either sex. Collagen content was also markedly elevated in the bladders of <i>ob</i>/<i>ob</i> mice. Void spot assays in filter paper in conscious mice revealed significant increases in total void volume and volume per void in <i>ob</i>/<i>ob</i> mice with no alterations of spot number. Treatment with ALT-711 significantly reduced the levels of MGO, AGEs, RAGE, and collagen content in <i>ob</i>/<i>ob</i> mice. In addition, ALT-711 treatment normalized the volume per void and increased the number of spots in <i>ob</i>/<i>ob</i> mice. Activation of AGEs-RAGE pathways by MGO in the bladder wall may contribute to the pathogenesis of diabetes-associated bladder dysfunction.<b>NEW & NOTEWORTHY</b> The involvement of methylglyoxal (MGO) and advanced glycation end products (AGEs) in bladder dysfunction of diabetic <i>ob/ob</i> mice treated with the AGE breaker ALT-711 was investigated here. Diabetic mice exhibited high levels of MGO, AGEs, receptor for AGEs (RAGE), and collagen in serum and/or bladder tissues along with increased volume per void, all of which were reduced by ALT-711. Activation of the MGO-AGEs-RAGE pathway in the bladder wall contributes to the pathogenesis of diabetes-associated bladder dysfunction.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 4","pages":"F436-F447"},"PeriodicalIF":4.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of renal sympathetic control using invasive pressure and flow velocity measurements in humans.","authors":"Didier Collard,&nbsp;Lennart van de Velde,&nbsp;Valerie E Stegehuis,&nbsp;Ronak Delewi,&nbsp;Marcel A M Beijk,&nbsp;IJsbrand A J Zijlstra,&nbsp;Robbert J de Winter,&nbsp;Liffert Vogt,&nbsp;Bert-Jan H van den Born","doi":"10.1152/ajprenal.00031.2023","DOIUrl":"https://doi.org/10.1152/ajprenal.00031.2023","url":null,"abstract":"<p><p>Renal sympathetic innervation is important in the control of renal and systemic hemodynamics and is a target for pharmacological and catheter-based therapies. The effect of a physiological sympathetic stimulus using static handgrip exercise on renal hemodynamics and intraglomerular pressure in humans is unknown. We recorded renal arterial pressure and flow velocity in patients with a clinical indication for coronary or peripheral angiography using a sensor-equipped guidewire during baseline, handgrip, rest, and hyperemia following intrarenal dopamine (30 μg/kg). Changes in perfusion pressure were expressed as the change in mean arterial pressure, and changes in flow were expressed as a percentage with respect to baseline. Intraglomerular pressure was estimated using a Windkessel model. A total of 18 patients (61% male and 39% female) with a median age of 57 yr (range: 27-85 yr) with successful measurements were included. During static handgrip, renal arterial pressure increased by 15.2 mmHg (range: 4.2-53.0 mmHg), whereas flow decreased by 11.2%, but with a large variation between individuals (range: -13.4 to 49.8). Intraglomerular pressure increased by 4.2 mmHg (range: -3.9 to 22.1 mmHg). Flow velocity under resting conditions remained stable, with a median of 100.6% (range: 82.3%-114.6%) compared with baseline. During hyperemia, maximal flow was 180% (range: 111%-281%), whereas intraglomerular pressure decreased by 9.6 mmHg (interquartile range: 4.8 to 13.9 mmHg). Changes in renal pressure and flow during handgrip exercise were significantly correlated (ρ = -0.68, <i>P</i> = 0.002). Measurement of renal arterial pressure and flow velocity during handgrip exercise allows the identification of patients with higher and lower sympathetic control of renal perfusion. This suggests that hemodynamic measurements may be useful to assess the response to therapeutic interventions aimed at altering renal sympathetic control.<b>NEW & NOTEWORTHY</b> Renal sympathetic innervation is important in the homeostasis of systemic and renal hemodynamics. We showed that renal arterial pressure significantly increased and that flow decreased during static handgrip exercise using direct renal arterial pressure and flow measurements in humans, but with a large difference between individuals. These findings may be useful for future studies aimed to assess the effect of interventions that influence renal sympathetic control.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 3","pages":"F263-F270"},"PeriodicalIF":4.2,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10400836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary anions control potassium excretion: it is more than a poorly absorbable anion effect.","authors":"Lama Al-Qusairi, Mohammed Z Ferdaus, Truyen D Pham, Dimin Li, P Richard Grimm, Ava M Zapf, Delaney C Abood, Ebrahim Tahaei, Eric Delpire, Susan M Wall, Paul A Welling","doi":"10.1152/ajprenal.00193.2023","DOIUrl":"10.1152/ajprenal.00193.2023","url":null,"abstract":"<p><p>The urinary potassium (K⁺) excretion machinery is upregulated with increasing dietary K⁺, but the role of accompanying dietary anions remains inadequately characterized. Poorly absorbable anions, including [Formula: see text], are thought to increase K⁺ secretion through a transepithelial voltage effect. Here, we tested if they also influence the K⁺ secretion machinery. Wild-type mice, aldosterone synthase (AS) knockout (KO) mice, or pendrin KO mice were randomized to control, high-KCl, or high-KHCO₃ diets. The K⁺ secretory capacity was assessed in balance experiments. Protein abundance, modification, and localization of K⁺-secretory transporters were evaluated by Western blot analysis and confocal microscopy. Feeding the high-KHCO₃ diet increased urinary K⁺ excretion and the transtubular K⁺ gradient significantly more than the high-KCl diet, coincident with more pronounced upregulation of epithelial Na+ channels (ENaC) and renal outer medullary K⁺ (ROMK) channels and apical localization in the distal nephron. Experiments in AS KO mice revealed that the enhanced effects of [Formula: see text] were aldosterone independent. The high-KHCO₃ diet also uniquely increased the large-conductance Ca²⁺-activated K⁺ (BK) channel β₄-subunit, stabilizing BKα on the apical membrane, the Cl^-/[Formula: see text] exchanger, pendrin, and the apical KCl cotransporter (KCC3a), all of which are expressed specifically in pendrin-positive intercalated cells. Experiments in pendrin KO mice revealed that pendrin was required to increase K⁺ excretion with the high-KHCO₃ diet. In summary, [Formula: see text] stimulates K⁺ excretion beyond a poorly absorbable anion effect, upregulating ENaC and ROMK in principal cells and BK, pendrin, and KCC3a in pendrin-positive intercalated cells. The adaptive mechanism prevents hyperkalemia and alkalosis with the consumption of alkaline ash-rich diets but may drive K⁺ wasting and hypokalemia in alkalosis.<b>NEW & NOTEWORTHY</b> Dietary anions profoundly impact K⁺ homeostasis. Here, we found that a K⁺-rich diet, containing [Formula: see text] as the counteranion, enhances the electrogenic K⁺ excretory machinery, epithelial Na⁺ channels, and renal outer medullary K⁺ channels, much more than a high-KCl diet. It also uniquely induces KCC3a and pendrin, in B-intercalated cells, providing an electroneutral KHCO₃ secretion pathway. These findings reveal new K⁺ balance mechanisms that drive adaption to alkaline and K⁺-rich foods, which should guide new treatment strategies for K⁺ disorders.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"325 3","pages":"F377-F393"},"PeriodicalIF":3.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10639028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10059294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}