Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Abstract Glomerular podocytes are integral members of the glomerular filtration barrier in the kidney and are crucial for glomerular permselectivity. These highly differentiated cells are vulnerable to an array of noxious stimuli that prevail in several glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetes. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. Previous studies have shown that podocytes express GH receptor (GHR) and induce Notch signalling when exposed to GH. In the present study, we demonstrate that GH induces TGF-β1 signalling and provokes cell cycle re-entry of otherwise quiescent podocytes. Though differentiated podocytes re-enter the cell cycle in response to GH and TGF-β1, they cannot accomplish cytokinesis, despite karyokinesis. Owing to this aberrant cell-cycle event, GH or TGF-β1 treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of JAK2, TGFBR1, or Notch prevented cell cycle re-entry of podocytes and protected from mitotic catastrophe associated cell death. Inhibition of Notch ac-tivation prevents GH-dependent podocyte injury and proteinuria. Similarly, attenuation of GHR expression abated Notch activation in podocytes. Kidney biopsy sections from patients with diabetic nephropathy show activation of Notch signalling and bi-nucleated podocytes. These data indicate that excess GH induced TGF-β1 dependent Notch1 signalling contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signalling in podocytopathy and the potential application of TGF-β1 or Notch inhibitors as a therapeutic agent for diabetic nephropathy.