Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension (original) (raw)
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The regulation of proximal tubular salt transport in hypertension: an update
Current Opinion in Nephrology and Hypertension, 2009
Purpose of review-Renal proximal tubular sodium reabsorption is regulated by sodium transporters, including the sodium glucose transporter, sodium amino acid transporter, sodium hydrogen exchanger isoform 3 and sodium phosphate cotransporter type 2 located at the luminal/ apical membrane, and sodium bicarbonate cotransporter and Na + /K + ATPase located at the basolateral membrane. This review summarizes recent studies on sodium transporters that play a major role in the increase in blood pressure in essential/polygenic hypertension. Recent findings-Sodium transporters and Na + /K + ATPase are segregated in membrane lipid and nonlipid raft microdomains that regulate their activities and trafficking via cytoskeletal proteins. The increase in renal proximal tubule ion transport in polygenic hypertension is primarily due to increased activity of NHE3 and Cl/HCO 3 exchanger at the luminal/apical membrane and a primary or secondary increase in Na + /K + ATPase activity.
Journal of Biological Chemistry, 2011
We have observed that, in renal proximal tubular cells, cardiotonic steroids such as ouabain in vitro signal through Na/K-ATPase, which results in inhibition of transepithelial 22 Na ؉ transport by redistributing Na/K-ATPase and NHE3. In the present study, we investigate the role of Na/K-ATPase signaling in renal sodium excretion and blood pressure regulation in vivo. In Sprague-Dawley rats, high salt diet activated c-Src and induced redistribution of Na/K-ATPase and NHE3 in renal proximal tubules. In Dahl salt sensitive (S) and resistant (R) rats given high dietary salt, we found different effects on blood pressure but, more interestingly, different effects on renal salt handling. These differences could be explained by different signaling through the proximal tubular Na/K-ATPase. Specifically, in Dahl R rats, high salt diet significantly stimulated phosphorylation of c-Src and ERK1/2, reduced Na/K-ATPase activity and NHE3 activity, and caused redistribution of Na/K-ATPase and NHE3. In contrast, these adaptations were either much less effective or not seen in the Dahl S rats. We also studied the primary culture of renal proximal tubule isolated from Dahl S and R rats fed a low salt diet. In this system, ouabain induced Na/K-ATPase/c-Src signaling and redistribution of Na/K-ATPase and NHE3 in the Dahl R rats, but not in the Dahl S rats. Our data suggested that impairment of Na/K-ATPase signaling and consequent regulation of Na/K-ATPase and NHE3 in renal proximal tubule may contribute to salt-induced hypertension in the Dahl S rat. . 2 The abbreviations used are: BP, blood pressure; CTS, cardiotonic steroids; EE, early endosome; ERK1/2, extracellular signal-regulated kinases 1 and 2; MBG, marinobufagenin; NHE3, sodium/hydrogen exchanger isoform 3; RPT, renal proximal tubule; HS, high salt diet; LS, low salt diet.
The Sodium Chloride Cotransporter (NCC) and Epithelial Sodium Channel (ENaC) Associate
The Biochemical journal, 2016
The thiazide-sensitive sodium chloride cotransporter (NCC) and the Epithelial Sodium Channel (ENaC) are two of the most important determinants of salt balance and thus systemic blood pressure. Abnormalities in either result in profound changes in blood pressure. There is one segment of the nephron where these two sodium transporters are co-expressed, the second part of the Distal Convoluted Tubule. This is a key part of the aldosterone-sensitive distal nephron, the final regulator of salt handling in the kidney. Aldosterone is the key hormonal regulator for both of these proteins. Despite these shared regulators and co-expression in a key nephron segment, associations between these proteins have not been investigated. After confirming apical localization of these proteins, we demonstrated the presence of functional transport proteins and native association by Blue Native PAGE. Extensive co-immunoprecipitation experiments demonstrated a consistent interaction of NCC with alpha and ga...
Reversible effects of acute hypertension on proximal tubule sodium transporters
American Journal of Physiology-Cell Physiology, 1998
Acute hypertension provokes a rapid decrease in proximal tubule sodium reabsorption with a decrease in basolateral membrane sodium-potassium-ATPase activity and an increase in the density of membranes containing apical membrane sodium/hydrogen exchangers (NHE3) [Y. Zhang, A. K. Mircheff, C. B. Hensley, C. E. Magyar, D. G. Warnock, R. Chambrey, K.-P. Yip, D. J. Marsh, N.-H. Holstein-Rathlou, and A. A. McDonough. Am. J. Physiol.270 ( Renal Fluid Electrolyte Physiol.39): F1004–F1014, 1996]. To determine the reversibility and specificity of these responses, rats were subjected to 1) elevation of blood pressure (BP) of 50 mmHg for 5 min, 2) restoration of normotension after the first protocol, or 3) sham operation. Systolic hypertension increased urine output and endogenous lithium clearance three- to fivefold within 5 min, but these returned to basal levels only 15 min after BP was restored. Renal cortex lysate was fractionated on sorbitol gradients. Basolateral membrane sodium-potassiu...
Kidney International, 1990
Adrenergic regulation of (Na, K)-ATPase activity in proximal tubules of spontaneously hypertensive rats. Increased renal nerve activity and sodium retention have been implicated in the development of hypertension in genetically transmitted forms of this disease. The present studies were designed to investigate the relationship between renal nerve integrity and renal proximal tubule (Na, K)-ATPase activity in spontaneously hypertensive rats (SUR). (Na, Ki-ATPase activity of basolateral membranes (BLMs) enriched from proximal tubules of five-week-old SHR was greater, 328.6 18.9 nmol P/mg protein. mm, than in age-matched genetic controls rats (Wystar-Kyoto, WKY, rats), 262.3 34.6 nmol P/mg protein. mm (P < 0.02). There was no detectable difference in (Na, K)-ATPase activity of 13-week-old SHR and WKY rats. Prior renal denervation was associated with a reduction in proximal tubule basolateral membrane (BLM) (Na, K)-ATPase activity, 316.8 23.8 to 223,1 23.9 nmol P,/mg protein/mm (P < 0.02), in five-week SHR. However, denervation had no effect on renal (Na, K)-ATPase activity in either WKY rats, nor did sham-denervation in SHR. In addition, exogenous norepinephrine, 1 /.LM, produced a more pronounced stimulation of (Na, K)-ATPase activity in basolateral membranes from SHR as opposed to WKY controls (40.2% vs. 28.7%). Therefore, renal nerve integrity and exogenous catecholamines have a greater stimulatory influence on proximal tubule (Na, K)-ATPase activity in the early stages (prior to 5 weeks) of the development of hypertension in SHR than in age-matched WKY rats. These findings suggest that increased renal nerve activity and enhancement of proximal tubule (Na, K)-ATPase activity by catecholamines may contribute to salt retention and the development of hypertension in the SHR model of hypertension. It is widely accepted that the kidney is involved primarily in the pathogenesis of genetic hypertension in rats. Central to this hypothesis is the observation that spontaneously hypertensive rats (SHR), as opposed to normotensive controls, retain sodium avidly prior to the development of hypertension [11. Furthermore, dietary sodium restriction retards the development of hypertension in SHR [2, 31. In addition, transplantation of kidneys from genetically similar normotensive rats into SHR normalizes blood pressure, while in contrast, transplantation of kidneys from hypertensive to normotensive rats is associated with the development of hypertension [41. Since renal nerve activity has been observed to be greater in SHR [5] and since increased efferent renal nerve activity
Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats
Journal of Pharmacology and Experimental Therapeutics, 2004
The purpose of this study was to compare the expression of BSC-1 (bumetanide-sensitive Na +-K +-2Clcotransporter) in kidneys of spontaneously hypertensive (SHR) versus Wistar-Kyoto (WKY) rats by immunoblotting and RT-PCR. To determine the specificity of any observed changes in BSC-1 expression, we also compared expression of the thiazide sensitive Na +-Clcotransporter (TSC), the type-3 Na +-H + exchanger (NHE-3), Na +-K +-ATPase-α 1 , the inwardly rectifying K + channel (ROMK-1), the type-1 Na +-HCO 3-cotransporter (NBC-1), aquaporin-1 and aquaporin-2. Analyses were performed on outer cortex, outer medulla and inner medulla. BSC-1 protein was detected in outer medulla and was markedly (6-fold) higher in SHR. TSC protein was detected in the cortex and was not over-expressed in SHR. Aquaporin-1 protein was detected in all three regions and was not over-expressed in SHR. Aquaporin-2 and ROMK-1 proteins were detected in all three regions, but were moderately elevated (2-fold) only in SHR inner medulla. Na +-K +-ATPase and NHE-3 proteins were detected in all three regions. Na +-K +-ATPase-α 1 was modestly (25%) increased in SHR outer and inner medulla, while NHE-3 was moderately (2-fold) increased in the SHR cortex and inner medulla. NBC-1 protein was detected only in the cortex, and was higher in SHR (2-fold). mRNA levels of BSC-1, aquaporin-2 and ROMK-1 were not elevated in SHR, indicating a post-translational mechanism of protein over-expression. High-dose furosemide increased fractional sodium excretion more in SHR than WKY (3-fold). We conclude that increased expression of BSC-1, and to a lesser extent, aquaporin-2, ROMK-1, NHE-3 and NBC-1, may contribute to the pathogenesis of hypertension in the SHR.
Hyperphosphorylation of Na-K-2Cl Cotransporter in Thick Ascending Limbs of Dahl Salt-Sensitive Rats
Hypertension, 2012
Salt-sensitive hypertension involves a renal defect preventing the kidney from eliminating excess NaCl. The thick ascending limb of Henle loop reabsorbs ≈30% of filtered NaCl via the apical Na-K-2Cl cotransporter (NKCC2). Higher NKCC2 activity and Cl reabsorption have been reported in the thick ascending limbs from Dahl salt-sensitive rats (DSS) fed normal salt. NKCC2 activity is primarily regulated by protein trafficking and phosphorylation at Thr 96 /Thr 101 via STE20- and SPS1-related proline and alanine-rich kinases and oxidative stress-responsive kinase 1. However, the mechanism for enhanced NKCC2 activity in DSS is unclear. We hypothesized that DSS exhibit enhanced NKCC2 trafficking and higher NKCC2 phosphorylation compared with Dahl salt-resistant rats on normal salt diet. We measured steady state surface NKCC2 expression and phosphorylation at Thr 96 and Thr 101 by surface biotinylation and Western blot. In DSS, the surface:total NKCC2 ratio was enhanced by 25% compared with...
Clinical and Experimental Pharmacology and Physiology, 2007
SUMMARY The renal bumetanide‐sensitive Na–K–2Cl cotransporter (BSC‐1) is expressed only in the thick ascending limb and selectively traffics from intracellular vesicles (IVs) to apical plasma membranes (PMs), where BSC‐1 regulates sodium reabsorption. We showed previously that in kidneys from adult spontaneously hypertensive rats (SHR; model of essential hypertension) total protein expression of BSC‐1 was higher compared with kidneys from normotensive Wistar‐Kyoto (WKY) rats. However, whether this change is associated with an increased trafficking of BSC‐1 from IVs to PMs is unknown. The goal of the present study was to test the hypothesis that the increase in total renal BSC‐1 protein expression in SHR is accompanied by an augmented distribution of BSC‐1 from IVs to PMs. To test the hypothesis, we obtained renal tissue from the inner stripe of the outer medulla (ISOM; enriched in thick ascending limbs) and isolated IVs and PMs from this tissue by differential centrifugation. Total ...
Physiological reports, 2014
Na,K-ATPase generates the driving force for sodium reabsorption in the kidney. Na,K-ATPase functional properties are regulated by small proteins belonging to the FXYD family. In kidney FXYD2 is the most abundant: it is an inhibitory subunit expressed in almost every nephron segment. Its absence should increase sodium pump activity and promote Na(+) retention, however, no obvious renal phenotype was detected in mice with global deletion of FXYD2 (Arystarkhova et al. 2013). Here, increased total cortical Na,K-ATPase activity was documented in the Fxyd2(-/-) mouse, without increased α1β1 subunit expression. We tested the hypothesis that adaptations occur in distal convoluted tubule (DCT), a major site of sodium adjustments. Na,K-ATPase immunoreactivity in DCT was unchanged, and there was no DCT hypoplasia. There was a marked activation of thiazide-sensitive sodium chloride cotransporter (NCC; Slc12a3) in DCT, predicted to increase Na(+) reabsorption in this segment. Specifically, NCC t...