Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Abstract

AbstractPodocytes are integral members of the filtration barrier in the kidney and are crucial for glomerular permselectivity. Podocytes are highly differentiated and vulnerable to an array of noxious stimuli during various clinical conditions whereas podocyte loss plays a key role in progressive glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetics. Previous studies have shown that podocytes express GH receptors (GHR), and induce Notch signaling when exposed to GH. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. In the present study, we demonstrate that GH induces cognate TGF-β1 signaling 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 unable to accomplish cytokinesis, despite nuclear division. Owing to this aberrant cell-cycle events significant amount of GH or TGF-β1 treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of GHR, TGFBR1, or Notch signaling prevented cell cycle re-entry and protects podocyte from cell death. Furthermore, inhibition of Notch activation prevents GH-dependent podocyte injury and proteinuria. Kidney biopsy sections from patients with diabetic nephropathy show activation of Notch signaling and bi-nucleated podocytes. All these data confirm that excess GH induces Notch1 signaling via TGF-β1 and contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signaling in the podocytopathy and the potential application of inhibitors of TGF-β1 or Notch inhibitors as a therapeutic agent for diabetic nephropathy.Significance StatementElevated circulating levels of growth hormone (GH) associated with glomerular hypertrophy and proteinuria. Whereas decreased GH action protected against proteinuria. Podocytes are highly differentiated cells that play a vital role in glomerular filtration and curb protein loss. The direct role of GH in podocytes is the focus of our study. We found that GH induces TGF-β1 and both provoke cell cycle re-entry of podocytes in Notch1 dependent manner. Notch activation enables the podocytes to accomplish karyokinesis, but not cytokinesis owing to which podocytes remain binucleated. Binucleated podocytes that were observed during GH/TGF-β1 treatment are susceptible to cell death. Our study highlighted the fact that enforcing the differentiated podocytes to re-enter the cell cycle results in mitotic catastrophe and permanent loss.