Temporal analysis of signaling pathways activated in a murine model of two-kidney, one-clip hypertension

1 Department of Experimental Pathology, ; 2 Department of Transplantation Biology, ; 3 Department of Nephrology and Hypertension, and ; 4 Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota Submitted July 25, 2008 ; accepted in final form July 16, 2009 Unilateral renal artery stenosis (RAS) leads to atrophy of the stenotic kidney and compensatory enlargement of the contralateral kidney. Although the two-kidney, one-clip (2K1C) model has been extensively used to model human RAS, the cellular responses in the stenotic and contralateral kidneys, particularly in the murine model, have received relatively little attention. We studied mice 2, 5, and 11 wk after unilateral RAS. These mice became hypertensive within 1 wk. The contralateral kidney increased in size within 2 wk after surgery. This enlargement was associated with a transient increase in expression of phospho-extracellular signal-regulated kinase (p-ERK), the proliferation markers proliferating cell nuclear antigen and Ki-67, the cell cycle inhibitors p21 and p27, and transforming growth factor-β, with return to baseline levels by 11 wk. The size of the stenotic kidney was unchanged at 2 wk but progressively decreased between 5 and 11 wk. Unlike the contralateral kidney, which showed minimal histopathological alterations, the stenotic kidney developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Surprisingly, the stenotic kidney showed a proliferative response, which involved largely tubular epithelial cells. The atrophic kidney had little evidence of apoptosis, despite persistent upregulation of p53; expression of cell cycle regulatory proteins in the stenotic kidney was persistently increased through 11 wk. These studies indicate that in the 2K1C model, the stenotic kidney and contralateral, enlarged kidney exhibit a distinct temporal expression of proteins involved in cell growth, cell survival, apoptosis, inflammation, and fibrosis. Notably, an unexpected proliferative response occurs in the stenotic kidney that undergoes atrophy. renal artery stenosis; atrophy; hypertrophy/hyperplasia; inflammation; fibrosis Address for reprint requests and other correspondence: J. P. Grande, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 (e-mail: grande.joseph{at}mayo.edu ).