IMBECU   20882
INSTITUTO DE MEDICINA Y BIOLOGIA EXPERIMENTAL DE CUYO
Unidad Ejecutora - UE
artículos
Título:
RhoA and MAPKinase signal transduction pathways regulate NHE1 Na+ /H+ 3 4 exchanger-dependent proximal tubule cell apoptosis following mechanical stretch
Autor/es:
VICTORIA BOCANEGRA ; ANDREA FERNANDA GIL LORENZO ; VALERIA CACCIAMANI; MARÍA EUGENIA BENARDÓN; VALERIA VICTORIA COSTANTINO; PATRICIA G VALLÉS
Revista:
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Editorial:
AMER PHYSIOLOGICAL SOC
Referencias:
Lugar: Bethesda; Año: 2014 p. 10 - 20
ISSN:
1931-857X
Resumen:
Mechanical deformation following congenital ureteral obstruction is traduced into biochemical signals leading to tubular atrophy due to epithelial cell apoptosis. We investigated whether the Na+/H+ exchanger, NHE1, could be responsible for HK-2 cell apoptosis induction, in response to mechanical stretch through its ability to function as a control point of RhoA and MAPKinase signaling pathways. When mechanical stretch was applied to HK-2 cells, cell apoptosis was associated with diminished NHE1 expression and RhoA activation. The RhoA signaling pathway was confirmed to be upstream from the MAPKinase cascade when HK-2 cells were transfected with the active RhoA-V14 mutant, showing higher ERK 1/2 expression and decreased p38 activation associated with NHE1 downregulation. NHE1 participation in apoptosis induction was confirmed by specific siRNA-NHE1 showing caspase-3 activation and decreased Bcl2 expression. The decreased NHE1 expression was correlated with the abnormal NHE1 activity addressed by the pHi measurement. These results demonstrate that mitochondrial proximal tubule cell apoptosis in response to mechanical stretch is orchestrated by signaling pathways initiated by the small GTPase RhoA and followed by the opposing effects of ERK 1/2 and p38 MAPKinase phosphorylation, regulating NHE1 decreased expression and activity.