Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure (original) (raw)
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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...
Chronic renal injury-induced hypertension alters renal NHE3 distribution and abundance
American Journal of …, 2003
phenol injection provokes acute sympathetic nervous systemdependent hypertension and a shift of proximal tubule Na ϩ /H ϩ exchanger isoform 3 (NHE3) and Na ϩ-Pi cotransporter type 2 (NaPi2) to apical microvilli. This study aimed to determine whether proximal tubule (PT) Na ϩ transporter redistribution persists chronically and whether the pool sizes of renal Na ϩ transporters are altered. At 5 wk after a 50-l 10% phenol injection, blood pressure is elevated: 154 Ϯ 8 vs. 113 Ϯ 11 mmHg after saline injection. Cortical membranes were fractionated into three "windows" enriched in apical brush border (WI), mixed apical and intermicrovillar cleft (WII), and intracellular membranes (WIII). NHE3 relative distribution in these windows, assessed by immunoblots and expressed as %total, remained shifted to apical from intracellular membranes (WI: 25.3 Ϯ 3 in phenol vs.12.7 Ϯ 3% in saline and WIII: 9.1 Ϯ 1.3 in phenol vs. 18.9 Ϯ 3% in saline). NaPi2 and dipeptidyl-peptidase IV also remained shifted to WI, and alkaline phosphatase activity increased 100.9 Ϯ 29.7 (WI) and 51.4 Ϯ 17.5% (WII) in phenol-injected membranes. Na ϩ transporter total abundance [NHE3, NaPi2, thiazidesensitive Na-Cl cotransporter, bumetanide-sensitive Na-K-2Cl cotransporter, Na-K-ATPase ␣ 1-and 1-subunits, and epithelial Na ϩ channel (ENaC) ␣and -subunits] was profiled by immunoblotting. Only cortical NHE3 abundance was altered, decreasing to 0.56 Ϯ 0.06. The results demonstrate that phenol injury provokes a persistant shift of PT NHE3 and NaPi2 to the apical microvilli, along with a 44% decrease in total NHE3, evidence for an escape mechanism that would counteract the redistribution of a larger fraction of NHE3 to the apical surface by normalizing the total amount of NHE3 in apical membranes. sodium transport; membrane traffic; sympathetic nervous system; phenol A MODEL OF NEUROGENIC HYPERTENSION provoked by intrarenal injection of phenol into the cortex of a pole of one kidney was recently developed by Ye and Campese (8, 33, 34). In this model, a 50-l 10% phenol injection causes a rapid elevation of blood pressure, preceded by
Pathogenesis of Sodium and Water Retention in Cardiac Failure
Renal Failure, 1998
The pathophysiology of sodium and water retention in heart failure is discussed in the context of a unijiing h.vpothesis of body fluid volume regulation. Critical to this hypothesis is the maintenance of arterial circulatory integritv, which can be disturbed by either a reduction in cardiac output or a fall in systemic vascular resistance secondary to arterial vasodilatation, as seen in high output heart failure. The filling ofthe arterial circulation is sensed b.y receptors in the left ventricle, carotid artery, aortic arch and renal afferent arteriole. Effector mechanisms involve non-osmotic vasopressin synthesis and release, the reninangiotensin-aldosterone system and the sympathetic nervous system. In low output heart failure non-peptide selective oralIv active vasopressin V2-receptor antagonists correct the hyponatremia, h,vpoosniolality, and water retention and decrease urinary aquaporin-2 water channels, supporting the role of vasopressin in the water retention seen in heart failure. In advanced heart failure aldosterone escape does not occur hecause of diminished distal delivery of sodium which also contributes to the resistance to atrial natriuretic peptide seen in heart failure. In high output cardiac failure arterial underjlling associated with arterial vasodilation stimulates activation of neurohunioral qstems. Tailored specijic selective inhibition of these neurohumoral Vstems, perhaps in combination, ma?/ enable more effective treatment of cardiac failure.
Hypertension (Dallas, Tex. : 1979), 2018
The present study directly tested the hypothesis that deletion of the NHE3 (Na/H exchanger 3) selectively in the proximal tubules of the kidney lowers basal blood pressure by increasing the pressure-natriuresis response in mice. Adult male and female, age-matched wild-type (WT) littermates and proximal tubule-specific NHE3 knockout mice (PT- Nhe3; n=6-16 per group) were studied for (1) basal phenotypes of electrolytes and pH, blood pressure, and kidney function; (2) the pressure-natriuresis response using the mesenteric, celiac, and abdominal arterial occlusion technique; and (3) the natriuretic responses to acute saline expansion (0.9% NaCl, 10% body weight, intraperitoneal) or 2-week of 2% NaCl diet. Under basal conditions, PT- Nhe3 mice showed significantly lower systolic, diastolic, and mean arterial blood pressure ( P<0.01) than WT mice ( P<0.01). PT- Nhe3 mice also exhibited significantly greater diuretic ( P<0.01) and natriuretic responses than WT mice ( P<0.01), ...
American Journal of Physiology - Cell Physiology, 2015
Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-depend...
The Journal of Physiology, 2003
The apical Na + -H + exchanger isoform 3 (NHE3) plays an important role in NaCl, HCO 3 _ and fluid reabsorption in the kidney proximal tubule and intestine, and thus is essential to the regulation of extracellular fluid volume and blood pressure. The deletion of the Slc9a3 gene encoding the NHE3 protein in mouse is associated with a mild diarrhoea and a significant defect in HCO 3 _ and fluid reabsorption by the proximal tubule ). The decreased HCO 3 _ reclamation in the proximal tubule is compensated in the collecting duct through an enhanced rate of bicarbonate absorption that is mediated via an adaptive increase in the expression of gastric H + -K + -ATPase and Cl _ -HCO 3 _ exchanger (AE1) as well as increased H + -ATPase activity . This adaptation has limited the perturbation of acid-base status of NHE3 null mice to a mild metabolic acidosis as shown by a small decrease in serum HCO 3 _ concentration and blood pH ). In addition, a decrease in glomerular filtration rate (GFR) and the upregulation of proximal tubule Na + -P i cotransporter (NaPi2) and collecting duct g-subunit of the epithelium Na + channel (ENAC) has been thought to compensate for decreased Na + reabsorption in the proximal tubule of NHE3 knockout mice . The absorptive defect in the intestine of homozygous mutant mice is also compensated to a certain degree in the distal colon via an adaptive increase in the activity and expression of the epithelial Na + channel and colonic H + -K + -ATPase ). In addition, mice lacking NHE3 exhibited significant volume depletion as shown by decreased blood pressure, increased kidney renin mRNA expression and elevated serum aldosterone levels . In light of these observations, we hypothesized that the processes involved in the urinary concentrating mechanism should be stimulated in order to compensate for defective water retention in the proximal tubule, and thus minimize water loss by the kidney.