Arterial wall hypertrophy is ameliorated by alpha 2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice

Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg (-/-)) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-beta 1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-beta 1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required. We performed renal denervation and administered the alpha 2-adrenergic receptor (AR) antagonist, atipamezole, to Atg (-/-) mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-beta 1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis. Norepinephrine content in kidneys of Atg (-/-) mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-beta 1 gene in kidneys of Atg (-/-) mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced alpha 2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg (-/-) mice, which lack renin substrate. Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg (-/-) mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of alpha 2-ARs. Although renal arterial hypertrophy in Atg (-/-) mice appears to be of multifactorial origin, TGF-beta 1 may play a key role in the persistence of such hypertrophy.