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Kidney Week

Abstract: TH-PO909

Activation of Notch Signaling in Podocytes by Growth Hormone

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Nishad, Rajkishor, University of Hyderabad, Hyderabad, India
  • Pasupulati, Anil Kumar, University of Hyderabad, Hyderabad, India
Background


Growth hormone (GH) plays a significant role in normal renal function and overactive GH signaling has been implicated in nephropathy particularly in diabetes and acromegaly. Previous results have shown that podocytes, which play an essential role in kidney filtration, express the GH receptor (GHR), suggesting the direct action of GH on these cells. Activation of Notch signaling, which is crucial in early podocyte development, contributes to the glomerular disease upon maturation. In this study, we investigated whether GH activates Notch1 signaling in podocytes in γ-secretase dependent manner.

Methods


Swiss Webster male mice were infused with GH i.p (1.5mg/kg/day) for 4 weeks. Another group of mice was administered GH and DAPT (10 mg/kg/day) while control mice received PBS. Renal functional and histological studies were performed at the end of the experimental period. Simultaneously, human podocytes (HPC) were treated with GH (500ng/ml) in the absence or presence of DAPT (5μg/ml) and assessed the expression of Notch signaling and its downstream targets.

Results


Employing HPC in vitro and GH-injected mice model in vivo, we demonstrate that GH activates Notch1 signaling in a γ-secretase-dependent manner in podocytes. Pharmacological inhibition of Notch1 by a γ-secretase inhibitor (DAPT) abrogated GH-induced epithelial to mesenchymal transition (EMT) and associated podocyte injury. Importantly, our results show that DAPT treatment blocked the GH-induced cytokine release and attenuated glomerulosclerosis. Further, DAPT prevented glomerular basement membrane thickening as well as proteinuria induced by GH. Kidney biopsy sections from diabetic nephropathy patients reveal activation of Notch signaling in podocytes.

Conclusion


GH induces Notch1 signaling in podocytes, which may contribute to proteinuria through podocyte EMT as well as renal fibrosis. Blocking Notch activation with γ-secretase inhibitors ameliorates glomerular injury and proteinuria in conditions of GH-associated nephropathy.

Funding

  • Government Support - Non-U.S.