Chronic renal injury-induced hypertension alters renal NHE3 distribution and abundance

Abstract

Renal cortical phenol injection provokes acute sympathetic nervous system-dependent hypertension and a shift of proximal tubule Na+/H+ exchanger isoform 3 (NHE3) and Na+-Pi cotransporter type 2 (NaPi2) to apical microvilli. This study aimed to determine whether proximal tubule (PT) Na+ transporter redistribution persists chronically and whether the pool sizes of renal Na+transporters are altered. At 5 wk after a 50-μl 10% phenol injection, blood pressure is elevated: 154 ± 8 vs. 113 ± 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 ± 3 in phenol vs.12.7 ± 3% in saline and WIII: 9.1 ± 1.3 in phenol vs. 18.9 ± 3% in saline). NaPi2 and dipeptidyl-peptidase IV also remained shifted to WI, and alkaline phosphatase activity increased 100.9 ± 29.7 ( WI) and 51.4 ± 17.5% ( WII) in phenol-injected membranes. Na+ transporter total abundance [NHE3, NaPi2, thiazide-sensitive Na-Cl cotransporter, bumetanide-sensitive Na-K-2Cl cotransporter, Na-K-ATPase α1- and β1-subunits, and epithelial Na+ channel (ENaC) α- and β-subunits] was profiled by immunoblotting. Only cortical NHE3 abundance was altered, decreasing to 0.56 ± 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.

Dipeptidyl peptidase IV inhibition downregulates Na+-H+exchanger NHE3 in rat renal proximal tubule

“…Interestingly, a similar shift in the distribution of DPPIV itself was found in I40-treated rats confirming a functional link between these proteins. These findings are in agreement with a series of studies performed by the laboratory of Dr. A. McDonough in which NHE3 along with DPPIV are coordinately redistributed between the microdomains of the kidney brush border in response to both acute (25,49) and chronic stimuli (48,50).…”

Inhibition of the formation of EETs and 20-HETE with 1-aminobenzotriazole attenuates pressure natriuresis

“…However, this mechanism seems unlikely because of the lack of an electrochemical gradient for backdiffusion of Na ϩ in the proximal tubule, and the existing Cl Ϫ gradient favors reabsorption rather than backleak. The work of Magyar et al (37,38) and others (72,74,75,76,78,79), indicating that elevations in RPP are associated with a fall in Na ϩ -K ϩ -ATPase activity and internalization of the sodium/hydrogen exchanger (NHE)-3 from the brush border of the proximal tubule, has led to the suggestion that some signal-transduction pathway probably couples elevations in RPP to inhibition of the active transport of Na ϩ in the proximal tubule. However, the mechanisms by which elevations in RPP and RIHP inhibit Na ϩ reabsorption are unknown and remain one of the key unanswered questions in hypertension research.…”

Effect of renal injury-induced neurogenic hypertension on NO synthase, caveolin-1, AKt, calmodulin and soluble guanylate cyclase expressions in the kidney

“…We subsequently demonstrated that intrarenal injection of phenol results in activation of sympathetic nervous system and an immediate increase in renal tubular sodium reabsorption. The latter was associated with and mediated by redistribution of Na ϩ transporters from intermicrovillar cleft/intracellular membrane pools to apical membranes in proximal tubules (31). Together, these observations suggest that sodium retention may contribute to maintenance of HTN in phenol-induced renal injury.…”

“…The intrarenal lesion in this model results in activation of renal afferent sympathetic pathway, which integrates with central noradrenergic control systems, resulting in activation of renal efferent sympathetic pathway. The latter, in turn, raises arterial pressure by augmenting renal vascular resistance and tubular sodium reabsorption and by modulating pressure natriuresis (31). The role of activation of renal afferent sympathetic pathway in the pathogenesis of HTN in this model is enforced by the observations that renal afferent impulses are enhanced (33) and HTN is prevented by renal denervation before phenol injection (32).…”