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American Journal of Physiology. Renal... Oct 2022BAT1 (Slc6a19) mediates absorption of neutral amino acids in the small intestine and in the kidneys, where it is primarily expressed in early proximal tubules (S1-S2)....
BAT1 (Slc6a19) mediates absorption of neutral amino acids in the small intestine and in the kidneys, where it is primarily expressed in early proximal tubules (S1-S2). To determine the role of BAT1 in nephropathy induced by aristolochic acid (AA), which targets the proximal tubule, littermate female BAT1-deficient (), heterozygous (), and wild-type (WT) mice were administered AA (10 mg/kg ip) or vehicle every 3 days for 3 wk, and analyses were performed after the last injection or 3 wk later. Vehicle-treated mice lacking showed normal body and kidney weight and plasma creatinine versus WT mice. The urinary glucose-to-creatinine ratio (UGCR) and urinary albumin-to-creatinine ratio (UACR) were two to four times higher in vehicle-treated versus WT mice, associated with lesser expression of early proximal transporters Na-glucose cotransporter 2 and megalin, respectively. AA caused tubular injury independently of BAT1, including robust increases in cortical mRNA expression of , , and hepatitis A virus cellular receptor 1 (), downregulation of related proximal tubule amino acid transporters BAT2 (), BAT3 (), and , and modest histological tubular damage and a rise in plasma creatinine. Absence of BAT1, however, attenuated AA-induced cortical upregulation of mRNA markers of senescence (), inflammation [lipocalin 2 (), C-C motif chemokine ligand 2 (), and C-C motif chemokine receptor 2 ()], and fibrosis [tissue inhibitor of metallopeptidase 1 (), transforming growth factor-β1 (), and collagen type I-α ()], associated with lesser fibrosis staining, lesser suppression of proximal tubular organic anion transporter 1, restoration of Na-glucose cotransporter 2 expression, and prevention of the AA-induced fivefold increase in the urinary albumin-to-creatinine ratio observed in WT mice. The data suggest that proximal tubular BAT1 is important for the physiology of renal glucose and albumin retention but potentially deleterious for the kidney response following AA-induced kidney injury. Based on insights from studies manipulating glucose transport, the hypothesis has been proposed that inhibiting intestinal uptake or renal reabsorption of energy substrates has unique therapeutic potential to improve metabolic disease and kidney outcome in response to injury. The present study takes this idea to BAT1, the major transporter for neutral amino acids in the intestine and kidney, and shows that its absence attenuates aristolochic acid-induced nephropathy.
Topics: Albumins; Amino Acid Transport Systems, Neutral; Amino Acids, Neutral; Animals; Aristolochic Acids; Creatinine; Female; Fibrosis; Glucose; Kidney Diseases; Mice; RNA, Messenger
PubMed: 35979966
DOI: 10.1152/ajprenal.00181.2022 -
Frontiers in Endocrinology 2021Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening,... (Review)
Review
Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.
Topics: Animals; Biomarkers; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Kidney Tubules
PubMed: 34177803
DOI: 10.3389/fendo.2021.661185 -
Pediatric Nephrology (Berlin, Germany) Oct 2020Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at... (Review)
Review
Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
Topics: Bartter Syndrome; Chloride Channels; Gitelman Syndrome; Humans; Kidney Tubules, Distal; Loop of Henle; Mutation; Renal Reabsorption; Sodium
PubMed: 31664557
DOI: 10.1007/s00467-019-04371-y -
Journal of Cellular and Molecular... Nov 2019This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is... (Review)
Review
This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC-5, a Cl /H antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC-5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC-5 KO models suggests that ClC-5 mediates parathormone endocytosis from tubular fluid. In addition, ClC-5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.
Topics: Animals; Calcium; Dent Disease; Humans; Ion Channels; Ion Transport; Phosphates
PubMed: 31472005
DOI: 10.1111/jcmm.14590 -
Clinical and Experimental Nephrology May 2022Increasing evidence has suggested a clinical relevance of magnesium in the context of vascular calcification and mortality among patients with CKD. Hypomagnesemia is not... (Review)
Review
Increasing evidence has suggested a clinical relevance of magnesium in the context of vascular calcification and mortality among patients with CKD. Hypomagnesemia is not rare among non-dialysis CKD patients despite their decreased glomerular filtration rates; the prevalence rate was about 15% even in CKD stages G4 and G5. Among several potential causes of hypomagnesemia, tubular dysfunction/interstitial fibrosis may play a pivotal role in the development of hypomagnesemia in CKD, which impairs tubular magnesium reabsorption. Magnesium deficiency may, in turn, be involved in the progression of CKD. An in vitro study has revealed that magnesium deficiency aggravates tubular cell death and inflammation induced by phosphate load. In a cohort study of patients with CKD, low-serum magnesium levels enhanced the risk of end-stage kidney disease related to high-serum phosphate levels, suggesting a close relationship between magnesium deficiency and phosphate toxicity. More importantly, magnesium has a potent capacity to inhibit the calcification of vascular smooth muscle cells induced by phosphate. A randomized trial has shown the efficacy of oral magnesium oxide in retarding the progression of coronary artery calcification among non-dialysis CKD patients. Thus, magnesium might provide better cardiovascular prognosis; indeed, hemodialysis patients with mild hypermagnesemia exhibited the lowest mortality rate. Further randomized trials are needed to assess the impact of magnesium in terms of hard clinical outcomes among CKD patients.
Topics: Cohort Studies; Disease Progression; Female; Humans; Magnesium; Magnesium Deficiency; Male; Phosphates; Renal Insufficiency, Chronic; Vascular Calcification
PubMed: 35076791
DOI: 10.1007/s10157-022-02182-4 -
Frontiers in Physiology 2021Euryhaline teleosts exhibit major changes in renal function as they move between freshwater (FW) and seawater (SW) environments, thus tolerating large fluctuations in... (Review)
Review
Euryhaline teleosts exhibit major changes in renal function as they move between freshwater (FW) and seawater (SW) environments, thus tolerating large fluctuations in salinity. In FW, the kidney excretes large volumes of water through high glomerular filtration rates (GFR) and low tubular reabsorption rates, while actively reabsorbing most ions at high rates. The excreted product has a high urine flow rate (UFR) with a dilute composition. In SW, GFR is greatly reduced, and the tubules reabsorb as much water as possible, while actively secreting divalent ions. The excreted product has a low UFR, and is almost isosmotic to the blood plasma, with Mg, SO , and Cl as the major ionic components. Early studies at the organismal level have described these basic patterns, while in the last two decades, studies of regulation at the cell and molecular level have been implemented, though only in a few euryhaline groups (salmonids, eels, tilapias, and fugus). There have been few studies combining the two approaches. The aim of the review is to integrate known aspects of renal physiology (reabsorption and secretion) with more recent advances in molecular water and solute physiology (gene and protein function of transporters). The renal transporters addressed include the subunits of the Na, K- ATPase (NKA) enzyme, monovalent ion transporters for Na, Cl, and K (NKCC1, NKCC2, CLC-K, NCC, ROMK2), water transport pathways [aquaporins (AQP), claudins (CLDN)], and divalent ion transporters for SO , Mg, and Ca (SLC26A6, SLC26A1, SLC13A1, SLC41A1, CNNM2, CNNM3, NCX1, NCX2, PMCA). For each transport category, we address the current understanding at the molecular level, try to synthesize it with classical knowledge of overall renal function, and highlight knowledge gaps. Future research on the kidney of euryhaline fishes should focus on integrating changes in kidney reabsorption and secretion of ions with changes in transporter function at the cellular and molecular level (gene and protein verification) in different regions of the nephrons. An increased focus on the kidney individually and its functional integration with the other osmoregulatory organs (gills, skin and intestine) in maintaining overall homeostasis will have applied relevance for aquaculture.
PubMed: 33967835
DOI: 10.3389/fphys.2021.664588 -
American Journal of Physiology. Heart... Sep 2019Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a/CD68 M1 macrophages into the renal medulla....
Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a/CD68 M1 macrophages into the renal medulla. Renal inflammation is implicated in renal sodium retention and the development of hypertension. Renal denervation is known to decrease renal inflammation. The objective of this study was to determine the role of CD161a/CD68 macrophages and renal sympathetic nerves in cholinergic-hypertension and renal sodium retention. Bilateral renal nerve denervation (RND) and immune ablation of CD161a immune cells were performed in young prehypertensive spontaneously hypertensive rat (SHR) followed by infusion of either saline or nicotine (15 mg·kg·day) for 2 wk. Immune ablation was conducted by injection of unconjugated azide-free antibody targeting rat CD161a. Blood pressure was monitored by tail cuff plethysmography. Tissues were harvested at the end of infusion. Nicotine induced premature hypertension, renal expression of the sodium-potassium chloride cotransporter (NKCC2), increases in renal sodium retention, and infiltration of CD161a/CD68 macrophages into the renal medulla. All of these effects were abrogated by RND and ablation of CD161a immune cells. Cholinergic activation of CD161a immune cells with nicotine leads to the premature development of hypertension in SHR. The effects of renal sympathetic nerves on chemotaxis of CD161a macrophages to the renal medulla, increased renal expression of NKCC2, and renal sodium retention contribute to cholinergic hypertension. The CD161a immune cells are necessary and essential for this prohypertensive nicotine-mediated inflammatory response. This is the first study that describes a novel integrative physiological interaction between the adrenergic, cholinergic, and renal systems in the development of hypertension, describing data for the role of each in a genetic model of essential hypertension. Noteworthy findings include the prevention of nicotine-mediated hypertension following successful immune ablation of CD161a immune cells and the necessary role these cells play in the overexpression of the sodium-potassium-chloride cotransporter (NKCC2) in the renal medulla and renal sodium retention. Renal infiltration of these cells is demonstrated to be dependent on the presence of renal adrenergic innervation. These data offer a fertile ground of therapeutic potential for the treatment of hypertension as well as open the door for further investigation into the mechanism involved in inflammation-mediated renal sodium transporter expression. Taken together, these findings suggest immune therapy, renal denervation, and, possibly, other new molecular targets as having a potential role in the development and maintenance of essential hypertension.
Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Disease Models, Animal; Hypertension; Inflammation Mediators; Kidney; Macrophages; Male; NK Cell Lectin-Like Receptor Subfamily B; Nicotine; Nicotinic Agonists; Phenol; Rats, Inbred SHR; Renal Artery; Renal Reabsorption; Sodium; Solute Carrier Family 12, Member 1; Sympathectomy, Chemical
PubMed: 31172810
DOI: 10.1152/ajpheart.00234.2019 -
Clinical Journal of the American... Feb 2023Mg2+, the fourth most abundant cation in the body, serves as a co-factor for about 600 cellular enzymes. One third of ingested Mg2+ is absorbed from the gut through a...
Mg2+, the fourth most abundant cation in the body, serves as a co-factor for about 600 cellular enzymes. One third of ingested Mg2+ is absorbed from the gut through a saturable transcellular process and a concentration-dependent paracellular process. Absorbed Mg2+ is excreted by the kidney and maintains serum Mg2+ within a narrow range of 0.7 to 1.25 mmol/L. The reabsorption of Mg2+ by the nephron is characterized by paracellular transport in the proximal tubule and thick ascending limb. The nature of the transport pathways in the gut epithelia and thick ascending limb has emerged from an understanding of the molecular mechanisms responsible for rare monogenetic disorders presenting with clinical hypomagnesemia. These human disorders due to loss-of function mutations, in concert with mouse models have led to a deeper understanding of Mg2+ transport in the gut and renal tubule. This review focuses on the nature of the transporters and channels revealed by human and mouse genetics and how they are integrated into an understanding of human Mg2+ physiology.
PubMed: 36723340
DOI: 10.2215/CJN.0000000000000103