Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow

2013 ◽  
Vol 304 (5) ◽  
pp. F585-F600 ◽  
Author(s):  
Olivier Bonny ◽  
Aurélie Edwards
Keyword(s):  
Transient Receptor Potential ◽  
Collecting Duct ◽  
Receptor Potential ◽  
Distal Tubule ◽  
Sodium Reabsorption ◽  
Transient Receptor Potential Vanilloid ◽  
Transport Pathways ◽  
Complex Interactions ◽  
Calcium Reabsorption ◽  
Transient Receptor

We developed a mathematical model of Ca2+ transport along the late distal convoluted tubule (DCT2) and the connecting tubule (CNT) to investigate the mechanisms that regulate Ca2+ reabsorption in the DCT2-CNT. The model accounts for apical Ca2+ influx across transient receptor potential vanilloid 5 (TRPV5) channels and basolateral Ca2+ efflux via plasma membrane Ca2+-ATPase pumps and type 1 Na+/Ca2+ exchangers (NCX1). Model simulations reproduce experimentally observed variations in Ca2+ uptake as a function of extracellular pH, Na+, and Mg2+ concentration. Our results indicate that amiloride enhances Ca2+ reabsorption in the DCT2-CNT predominantly by increasing the driving force across NCX1, thereby stimulating Ca2+ efflux. They also suggest that because aldosterone upregulates both apical and basolateral Na+ transport pathways, it has a lesser impact on Ca2+ reabsorption than amiloride. Conversely, the model predicts that full NCX1 inhibition and parathyroidectomy each augment the Ca2+ load delivered to the collecting duct severalfold. In addition, our results suggest that regulation of TRPV5 activity by luminal pH has a small impact, per se, on transepithelial Ca2+ fluxes; the reduction in Ca2+ reabsorption induced by metabolic acidosis likely stems from decreases in TRPV5 expression. In contrast, elevations in luminal Ca2+ are predicted to significantly decrease TRPV5 activity via the Ca2+-sensing receptor. Nevertheless, following the administration of furosemide, the calcium-sensing receptor-mediated increase in Ca2+ reabsorption in the DCT2-CNT is calculated to be insufficient to prevent hypercalciuria. Altogether, our model predicts complex interactions between calcium and sodium reabsorption in the DCT2-CNT.

Soluble α-klotho anchors TRPV5 to the distal tubular cell membrane independent of FGFR1 by binding TRPV5 and galectin-1 simultaneously

2021 ◽  
Author(s):  
Jinho Lee ◽  
Kyung Don Ju ◽  
Hyo Jin Kim ◽  
Bodokhsuren Tsogbadrakh ◽  
Hyunjin Ryu ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Distal Tubule ◽  
Transient Receptor Potential Vanilloid ◽  
Calcium Excretion ◽  
Tubular Cells ◽  
Calcium Reabsorption ◽  
Transient Receptor

Hypercalciuria is one of early manifestations of diabetic nephropathy (DN). This is partially due to a decrease in the expression of renal transient receptor potential vanilloid type 5 (TRPV5), which is responsible for renal calcium reabsorption. Soluble klotho was previously determined to increase TRPV5 by cleaving sialic acid, causing TRPV5 to bind to membrane protein galectin-1. However, a recent study showed that soluble klotho binds to α2-3-sialyllactose - where sialic acid is located - on TRPV5, rather than cleave it. Here, we report that soluble klotho tethers TRPV5 on the membrane by binding both TRPV5 and galectin-1, thereby protecting membrane TRPV5 from diabetes-induced endocytosis. We injected recombinant soluble α-klotho protein (rKL) into db/db and db/m mice for 8 weeks and collected urine and the kidney. We administered rKL, AZD4547 (FGFR1 inhibitor), and OTX008 (Galectin 1 inhibitor) to cultured mouse distal tubular cells, with or without 30 mM high glucose (HG) exposure. db/db mice showed increased renal calcium excretion and decreased renal TRPV5 expression. rKL treatment reversed this change. In vitro, TRPV5 expression in distal tubular cells decreased under HG conditions, and rKL successfully upregulated TRPV5 with or without FGF23. Also, immunofluorescence showed co-localization of klotho, TRPV5, and galectin-1 in distal tubule cells, suggesting that klotho binds to both TRPV5 and galectin 1. Moreover, when both FGFR1 and galectin-1 were inhibited, rKL failed to increase TRPV5 under HG conditions. Our results indicate that soluble klotho prevents TRPV5 from degradation and subsequent diabetes-induced endocytosis by anchoring TRPV5 through binding with both TRPV5 and galectin-1.

scholarly journals Mechanosensor transient receptor potential vanilloid member 4 (TRPV4) regulates mouse cholangiocyte secretion and bile formation

2020 ◽  
Vol 318 (2) ◽  
pp. G277-G287
Author(s):  
Qin Li ◽  
Charles Kresge ◽  
Kristy Boggs ◽  
Julie Scott ◽  
Andrew Feranchak
Keyword(s):  
Fluid Flow ◽  
Bile Flow ◽  
Transient Receptor Potential ◽  
Atp Release ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Bile Formation ◽  
Transport Pathways ◽  
Transient Receptor

Mechanosensitive signaling has emerged as a mechanism for the regulation of cholangiocyte transport and bile formation. The mechanical effect of fluid-flow, or shear, at the apical membrane of cholangiocytes regulates secretion through a process involving increases in [Ca2+]i and activation of Ca2+-activated Cl− channels. However, the initiating steps translating shear force to increases in intracellular calcium concentration ([Ca2+]i) are unknown. Transient receptor potential vanilloid member 4 (TRPV4), a nonselective cation channel present in the apical membrane of cholangiocytes, has been proposed as a potential mechanosensor. The aim of the present studies was to determine the potential role of TRPV4 in initiating mechanosensitive signaling in response to fluid-flow in cholangiocytes. TRPV4 expression was confirmed in both small and large mouse cholangiocytes. Exposure of cells to either fluid flow or specific TRPV4 pharmacological agonists rapidly increased both [Ca2+]i and membrane cation currents. Both flow- and agonist-stimulated currents displayed identical biophysical properties and were inhibited in the presence of TRPV4 antagonists or in cells after transfection with TRPV4 small interfering RNA. Transfection of mouse cholangiocytes with a TRPV4-enhanced green fluorescent protein construct increased the expression of TRPV4 and the magnitude of flow-stimulated currents. A specific TRPV4 agonist significantly increased the biliary concentration of ATP and bile flow in live mice when administered intravenously and increased ATP release from cholangiocyte monolayers when applied exogenously. The findings are consistent with a model in which activation of cholangiocyte TRPV4 translates shear force into an acute rise in membrane cation permeability, [Ca2+]i, ATP release, and bile flow. Understanding the role of mechanosensitive transport pathways may provide novel insights to modulate bile flow for the treatment of cholestatic liver disorders. NEW & NOTEWORTHY These studies functionally characterize TRPV4 as a mechanosensitive channel in mouse cholangiocytes. By mediating a rapid rise in intracellular Ca2+, necessary for Ca2+-dependent secretion, TRPV4 represents a mechanosensor responsible for translating fluid flow into intracellular signaling and biliary secretion. Furthermore, intravenous infusion of a specific TRPV4 agonist increases bile flow in live mice. Understanding the role of TRPV4 in mechanosensitive transport pathways may provide novel insights to modulate bile flow during cholestasis.

scholarly journals Dynamic coupling between TRPV4 and Ca2+-activated SK1/3 and IK1 K+ channels plays a critical role in regulating the K+-secretory BK channel in kidney collecting duct cells

2017 ◽  
Vol 312 (6) ◽  
pp. F1081-F1089 ◽  
Author(s):  
Yue Li ◽  
Hongxiang Hu ◽  
Jin-Bin Tian ◽  
Michael X. Zhu ◽  
Roger G. O’Neil
Keyword(s):  
Membrane Potential ◽  
Transient Receptor Potential ◽  
Collecting Duct ◽  
Critical Role ◽  
Receptor Potential ◽  
Bk Channel ◽  
Transient Receptor Potential Vanilloid ◽  
Cortical Collecting Duct ◽  
Intracellular Ca ◽  
Transient Receptor

The large-conductance Ca2+-activated K+ channel, BK (KCNMA1), is expressed along the connecting tubule (CNT) and cortical collecting duct (CCD) where it underlies flow- and Ca2+-dependent K+ secretion. Its activity is partially under the control of the mechanosensitive transient receptor potential vanilloid type 4 (TRPV4) Ca2+-permeable channel. Recently, we identified three small-/intermediate-conductance Ca2+-activated K+ channels, SK1 (KCNN1), SK3 (KCNN3), and IK1 (KCNN4), with notably high Ca2+-binding affinities, that are expressed in CNT/CCD and may be regulated by TRPV4-mediated Ca2+ influx. The K+-secreting CCD mCCDcl1 cells, which express these channels, were used to determine whether SK1/3 and IK1 are activated on TRPV4 stimulation and whether they contribute to Ca2+ influx and activation of BK. Activation of TRPV4 (GSK1016790A) modestly depolarized the membrane potential and robustly increased intracellular Ca2+, [Ca2+]i. Inhibition of both SK1/3 and IK1 by application of apamin and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), respectively, further depolarized the membrane potential and markedly suppressed the TRPV4-mediated rise in [Ca2+]i. Application of BK inhibitor iberiotoxin after activation of TRPV4 without apamin/TRAM-34 also reduced [Ca2+]i and further intensified membrane depolarization, demonstrating BK involvement. However, the BK-dependent effects on [Ca2+]i and membrane potential were largely abolished by pretreatment with apamin and TRAM-34, identical to that observed by separately suppressing TRPV4-mediated Ca2+ influx, demonstrating that SK1/3-IK1 channels potently contribute to TRPV4-mediated BK activation. Our data indicate a direct correlation between TRPV4-mediated Ca2+ signal and BK activation but where early activation of SK1/3 and IK1 channels are critical to sufficiently enhanced Ca2+ entry and [Ca2+]i levels required for activation of BK.

scholarly journals Structure-based characterization of novel TRPV5 inhibitors

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Taylor ET Hughes ◽  
John Smith Del Rosario ◽  
Abhijeet Kapoor ◽  
Aysenur Torun Yazici ◽  
Yevgen Yudin ◽  
...  
Keyword(s):  
Rational Design ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Parent Compound ◽  
Specific Inhibitor ◽  
Receptor Potential ◽  
Selective Inhibition ◽  
Transient Receptor Potential Vanilloid ◽  
Calcium Reabsorption ◽  
Transient Receptor

Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we performed structure-based virtual screening (SBVS) at a previously identified TRPV5 inhibitor binding site coupled with electrophysiology screening and identified three novel inhibitors of TRPV5, one of which exhibits high affinity, and specificity for TRPV5 over other TRP channels, including its close homologue TRPV6. Cryo-electron microscopy of TRPV5 in the presence of the specific inhibitor and its parent compound revealed novel binding sites for this channel. Structural and functional analysis have allowed us to suggest a mechanism of action for the selective inhibition of TRPV5 and lay the groundwork for rational design of new classes of TRPV5 modulators.

scholarly journals TRPV4 deletion protects against hypokalemia during systemic K+ deficiency

2019 ◽  
Vol 316 (5) ◽  
pp. F948-F956 ◽  
Author(s):  
Viktor Tomilin ◽  
Mykola Mamenko ◽  
Oleg Zaika ◽  
Charles S. Wingo ◽  
Oleh Pochynyuk
Keyword(s):  
Transient Receptor Potential ◽  
Collecting Duct ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Clinical Settings ◽  
Deficient Diet ◽  
K Deficiency ◽  
Transient Receptor ◽  
Novel Strategy

Tight regulation of K+ balance is fundamental for normal physiology. Reduced dietary K+ intake, which is common in Western diets, often leads to hypokalemia and associated cardiovascular- and kidney-related pathologies. The distal nephron, and, specifically, the collecting duct (CD), is the major site of controlled K+ reabsorption via H+-K+-ATPase in the state of dietary K+ deficiency. We (Mamenko MV, Boukelmoune N, Tomilin VN, Zaika OL, Jensen VB, O'Neil RG, Pochynyuk OM. Kidney Int 91: 1398–1409, 2017) have previously demonstrated that the transient receptor potential vanilloid type 4 (TRPV4) Ca2+ channel, abundantly expressed in the CD, contributes to renal K+ handling by promoting flow-induced K+ secretion. Here, we investigated a potential role of TRPV4 in controlling H+-K+-ATPase-dependent K+ reabsorption in the CD. Treatment with a K+-deficient diet (<0.01% K+) for 7 days reduced serum K+ levels in wild-type (WT) mice from 4.3 ± 0.2 to 3.3 ± 0.2 mM but not in TRPV4−/− mice (4.3 ± 0.1 and 4.2 ± 0.3 mM, respectively). Furthermore, we detected a significant reduction in 24-h urinary K+ levels in TRPV4−/− compared with WT mice upon switching to K+-deficient diet. TRPV4−/− animals also had significantly more acidic urine on a low-K+ diet, but not on a regular (0.9% K+) or high-K+ (5% K+) diet, which is consistent with increased H+-K+-ATPase activity. Moreover, we detected a greatly accelerated H+-K+-ATPase-dependent intracellular pH extrusion in freshly isolated CDs from TRPV4−/− compared with WT mice fed a K+-deficient diet. Overall, our results demonstrate a novel kaliuretic role of TRPV4 by inhibiting H+-K+-ATPase-dependent K+ reabsorption in the CD. We propose that TRPV4 inhibition could be a novel strategy to manage certain hypokalemic states in clinical settings.

Sign in / Sign up

Export Citation Format

Share Document