title: RhoA and MAPK signal transduction pathways regulate NHE1-dependent proximal tubule cell apoptosis after mechanical stretch.
abstract: Mechanical deformation after congenital ureteral obstruction is traduced into biochemical signals leading to tubular atrophy due to epithelial cell apoptosis. We investigated whether Na(+)/H(+) exchanger 1 (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 MAPK 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 MAPK cascade when HK-2 cells were transfected with the active RhoA-V14 mutant, showing higher ERK1/2 expression and decreased p38 activation associated with NHE1 downregulation. NHE1 participation in apoptosis induction was confirmed by specific small interfering RNA NHE1 showing caspase-3 activation and decreased Bcl-2 expression. The decreased NHE1 expression was correlated with abnormal NHE1 activity addressed by intracellular pH measurements. 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 ERK1/2 and p38 MAPK phosphorylation, regulating NHE1 decreased expression and activity.
authors: Instituto de Medicina y Biología Experimental de Cuyo-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and.
authors: Victoria
authors: V
authors: Bocanegra
authors: Instituto de Medicina y Biología Experimental de Cuyo-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and.
authors: Andrea Fernanda
authors: AF
authors: Gil Lorenzo
authors: Área de Fisiología Patológica, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors: Valeria
authors: V
authors: Cacciamani
authors: Área de Fisiología Patológica, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors: María Eugenia
authors: ME
authors: Benardón
authors: Instituto de Medicina y Biología Experimental de Cuyo-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and.
authors: Valeria Victoria
authors: VV
authors: Costantino
authors: Instituto de Medicina y Biología Experimental de Cuyo-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and Área de Fisiología Patológica, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina pvalles@fcm.uncu.edu.ar.
authors: Patricia G
authors: PG
authors: Vallés
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D020239:Receptor Cross-Talk; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013314:Stress, Mechanical; D014517:Ureteral Obstruction / Q000201:enzymology* / Q000503:physiopathology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D017923:Sodium-Hydrogen Exchangers; D020742:rhoA GTP-Binding Protein
keywords: Na+/H+ exchanger 1; RhoA; apoptosis; mechanical stretch; mitogen-activated protein kinases; proximal tubule cell