Background. The kidney is the main organ in the pathophys- iology 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 reab- sorption. 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 ux. MicroRNA (miRNA) expression of hypertensive patients signi cantly di ers 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 identi ed miRNA expression pro les 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 identi ed, 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, transfec- tion 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 in uenced by high sodium intake in the mTALs of rats. The downregulation of miRNA- 23a in humans a ected 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.

miRNA-23a modulates sodium-hydrogen exchanger 1 expression: studies in medullary thick ascending limb of salt-induced hypertensive rats / Lombari, Patrizia; Mallardo, Massimo; Petrazzuolo, Oriana; Amruthraj Nagoth, Joseph; Fiume, Giuseppe; Scanni, Roberto; Iervolino, Anna; Damiano, Sara; Coppola, Annapaola; Borriello, Margherita; Ingrosso, Diego; Perna, Alessandra F.; Zacchia, Miriam; Trepiccione, Francesco; Capasso., Giovambattista. - In: NEPHROLOGY DIALYSIS TRANSPLANTATION. - ISSN 0931-0509. - (2023), pp. 1-13. [10.1093/ndt/gfac232]

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

Massimo Mallardo
;
Anna Iervolino;Sara Damiano;Francesco Trepiccione;
2023

Abstract

Background. The kidney is the main organ in the pathophys- iology 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 reab- sorption. 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 ux. MicroRNA (miRNA) expression of hypertensive patients signi cantly di ers 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 identi ed miRNA expression pro les 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 identi ed, 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, transfec- tion 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 in uenced by high sodium intake in the mTALs of rats. The downregulation of miRNA- 23a in humans a ected 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.
2023
miRNA-23a modulates sodium-hydrogen exchanger 1 expression: studies in medullary thick ascending limb of salt-induced hypertensive rats / Lombari, Patrizia; Mallardo, Massimo; Petrazzuolo, Oriana; Amruthraj Nagoth, Joseph; Fiume, Giuseppe; Scanni, Roberto; Iervolino, Anna; Damiano, Sara; Coppola, Annapaola; Borriello, Margherita; Ingrosso, Diego; Perna, Alessandra F.; Zacchia, Miriam; Trepiccione, Francesco; Capasso., Giovambattista. - In: NEPHROLOGY DIALYSIS TRANSPLANTATION. - ISSN 0931-0509. - (2023), pp. 1-13. [10.1093/ndt/gfac232]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/902594
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