Evidence of a role for fibroblast transient receptor potential canonical 3 Ca2+ channel in renal fibrosis

• Autores: Saliba, Youakim; Karam, Ralph; Smayra, Viviane; Aftimos, Georges; Abramowitz, Joel; Birnbaumer, Lutz; Farès, Nassim
• Año de publicación: 2015
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: American Society of Nephrology. 2015, 26(8)
• Materia: ENFERMEDADES RENALES; ENFERMEDADES CARDIOVASCULARES; FIBROSIS; CALCIO; CANALES IONICOS
• Institución: Pontificia Universidad Católica Argentina

Fil: Saliba, Youakim. Saint Joseph University. Faculty of Medicine. Pole of Technology and Health. Physiology and Pathophysiology Research Laboratory; Libano
Fil: Karam, Ralph. Saint Joseph University. Faculty of Medicine. Pole of Technology and Health. Physiology and Pathophysiology Research Laboratory; Libano
Fil: Smayra, Viviane. Saint Joseph University. Faculty of Medicine; Libano
Fil: Aftimos, Georges. National Institute of Pathology. Department of Anatomopathology; Libano
Fil: Abramowitz, Joel. National Institute of Environmental Health Sciences. Research Triangle Park. Laboratory of Neurobiology; Estados Unidos
Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Research Triangle Park. Laboratory of Neurobiology; Estados Unidos
Fil: Birnbaumer, Lutz. Pontificia Univerisdad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Farès, Nassim. Saint Joseph University. Faculty of Medicine. Laboratory of Physiology and Pathophysiology; Libano
Abstract: Transient receptor potential canonical (TRPC) Ca -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-snglycerol– induced Ca entry in these cells, which was detected by fura-2 Ca imaging. TRPC3 blockade or Ca removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.