Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Abstract

24Growth hormone (GH) had direct effects on the glomerular podocyte. Increased levels of GH 25 are implicated in the pathogenesis of renal abnormalities in acromegaly and in diabetic 26 nephropathy in Type 1 diabetes mellitus. We investigated the role of Transforming growth 27 factor-β1 (TGF-β1) in GH's effects on the glomerular podocyte. Exposure of podocytes to GH 28 resulted in elevated expression of TGF-β1 and was concurrent with increased phosphorylation 29 of SMAD2/3 and nuclear accumulation of SMAD4. Conditioned media from podocytes exposed 30 to GH also triggered SMAD signaling. Podocytes treated with GH showed increased 31 permeability to albumin. Mice injected with GH demonstrated increased kidney size, glomerular 32 hypertrophy, and proteinuria. The renal manifestations in GH injected mice were associated with 33 increased TGF-β1 expression and activation of TGF-β1 signaling pathways. Concurrent 34 administration of TGF-β receptor antagonist (SB431542) with GH abrogated these renal effects 35 of GH administration. These results reveal the role of TGF-β1 in GH's actions on the glomerular 36 podocyte and provide a novel mechanistic basis for GH-induced glomerular dysfunction in 37 clinical conditions such as diabetes and acromegaly. 38 39 40 41 42 43