Activation of Erk1/2 and Akt following unilateral ureteral obstruction.
Chronic unilateral ureteral obstruction is a well characterized model of renal injury leading to tubulointerstitial fibrosis and distinct patterns of cell proliferation and apoptosis in the obstructed kidney. In this study we assessed the contribution of the mitogen activated protein kinase (MAPK)-ERK1/2 and the phosphatidylinositol 3 kinase (PI3K)-Akt pathways to early renal changes following unilateral obstruction. Increased activation of small Ras GTPase and its downstream effectors ERK1/2 and Akt was detected in ligated kidneys. The use of specific pharmacological inhibitors to either ERK1/2 or Akt activation led to decreased levels of fibroblast-myofibroblast markers in the interstitium while inhibition of PI3K reduced the number of proliferating cells and the amount of interstitial extracellular matrix deposition. Treatment with an ERK1/2 inhibitor diminished the number of apoptotic tubule and interstitial cells. Our results suggest a role for the MAPK-ERK1/2 and PI3K-Akt systems in early changes induced by ureteral obstruction and that inhibition of these signaling pathways may provide a novel approach to prevent progression of renal fibrosis.
Rodríguez-Peña
Ana B
AB
Departamento de Fisiología y Farmacología, Instituto 'Reina Sofía' de Investigación Nefrológica, Universidad de Salamanca and Red de Investigación en Enfermedades Renales, RedinRen del Instituto Carlos III, Salamanca, Spain.
Grande
Maria T
MT
Eleno
Nélida
N
Arévalo
Miguel
M
Guerrero
Carmen
C
Santos
Eugerio
E
López-Novoa
José M
JM
D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D005355:Fibrosis; D007668:Kidney / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications / Q000201:enzymology* / Q000473:pathology
D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3