miRNA-23a modulates sodium-hydrogen exchanger 1 expression: studies in medullary thick ascending limb of salt-induced hypertensive rats.

BACKGROUND: The kidney is the main organ in the pathophysiology of essential hypertension. Although most bicarbonate reabsorption occurs in the proximal tubule, the medullary thick ascending limb (mTAL) of the nephron also maintains acid-base balance by contributing to 25% of bicarbonate reabsorption. A crucial element in this regulation is the sodium-hydrogen exchanger 1 (NHE1), a ubiquitous membrane protein controlling intracellular pH, where proton extrusion is driven by the inward sodium flux. MicroRNA (miRNA) expression of hypertensive patients significantly differs from that of normotensive subjects. The aim of this study was to determine the functional role of miRNA alterations at the mTAL level. METHODS: By miRNA microarray analysis, we identified miRNA expression profiles in isolated mTALs from high sodium intake-induced hypertensive rats (HSD) versus their normotensive counterparts (NSD). In vitro validation was carried out in rat mTAL cells. RESULTS: Five miRNAs involved in the onset of salt-sensitive hypertension were identified, including miR-23a, which was bioinformatically predicted to target NHE1 mRNA. Data demonstrated that miRNA-23a is downregulated in the mTAL of HSD rats while NHE1 is upregulated. Consistently, transfection of an miRNA-23a mimic in an mTAL cell line, using a viral vector, resulted in NHE1 downregulation. CONCLUSION: NHE1, a protein involved in sodium reabsorption at the mTAL level and blood pressure regulation, is upregulated in our model. This was due to a downregulation of miRNA-23a. Expression levels of this miRNA are influenced by high sodium intake in the mTALs of rats. The downregulation of miRNA-23a in humans affected by essential hypertension corroborate our data and point to the potential role of miRNA-23a in the regulation of mTAL function following high salt intake.

Hypertension and renal calcium transport.

Calcium homeostasis is altered in hypertensive patients. Indeed several investigators have reported that sodium-sensitive hypertension is associated with hypercalciuria. On the other hand, an independent clinical association exists between the occurrence of urolithiasis and hypertension, but the molecular mechanism(s) involved in stone formation by high blood pressure have not been so far clarified. To understand this association, it is obvious that we should analyze the effect of hypertension on the transport proteins involved in the renal calcium handling. In the kidney, the tubular reabsorption of calcium may proceed through transcellular and paracellular routes. At variance with the proximal tubule, along the distal segment, calcium transport is entirely sodium independent and occurs via the transcellular pathway. In particular, transcellular calcium reabsorption proceeds through a well-controlled sequence of events consisting of luminal calcium entry via the epithelial calcium channel (TRPV5), cytosolic diffusion of calcium bound to calbindin-D28K, and basolateral extrusion of calcium through the Na/Ca exchanger (NCX1) and plasma membrane Ca-ATPase (PMCA). It is highly likely that these proteins may be altered in hypertensive disease thus justifying and explaining the reported hypercalciuria. Experiments in hypertensive strains of animals exhibiting hypercalciuria may help to solve this puzzle.