Growth Hormone Induces Transforming Growth Factor‐Beta‐Induced Protein in Podocytes: Implications for Podocyte Depletion and Proteinuria

Abstract

The glomerular podocytes form a major size selective barrier for the filtration of serum proteins and reduced podocyte number is a critical event in the pathogenesis of proteinuria during diabetic nephropathy (DN). An elevated level of growth hormone (GH) is implicated as a causative factor in the development of nephropathy in patients with type 1 diabetes mellitus. We have previously shown that podocytes express GH receptor and are a target for GH action. To elucidate the molecular basis for the effects of GH on podocyte depletion, we conducted PCR-array analyses for extracellular matrix and adhesion molecules in podocytes. Our studies reveal that GH increases expression of a gene that encodes transforming growth factor-beta-induced protein (TGFBIp) expression. Similarly, microarray data retrieved from the Nephromine database revealed elevation of TGFBIp in patients with DN. Treatment with GH results in increased secretion of extracellular TGFBIp by podocytes. Both GH and TGFBIp induced apoptosis and epithelial mesenchymal transition (EMT) of podocytes. Exposure of podocytes to GH and TGFBIp resulted in increased migration of cells and altered podocyte permeability to albumin across podocyte monolayer. Administration of GH to rats induced EMT and apoptosis in the glomerular fraction of the kidney. Therefore, we conclude that the GH-dependent increase in TGFBIp in the podocyte is one of the mechanisms responsible for podocyte depletion in DN.

Novel Actions of Growth Hormone in Podocytes: Implications for Diabetic Nephropathy

“…MMP2 and MMP9 are the major matrix proteases associated with ECM turnover. In our earlier study, we employed ECM and adhesion molecules profiler PCR array and analyzed the effect of GH on the expression of 84 genes that are important for cell–cell and cell–matrix interactions (81). This array contains ECM proteins including BM constituents, collagens, and other genes defining ECM structure.…”

“…This array contains ECM proteins including BM constituents, collagens, and other genes defining ECM structure. GH induced the expression of collagen type II α1, integrin E, laminin subunit α3, and laminin subunit β3 (81). The data suggest that GH promotes increased synthesis of ECM components.…”

“…The data suggest that GH promotes increased synthesis of ECM components. Coincident with the synthesis of ECM components, GH treatment resulted in reduced expression of MMPs, such as MMP7 and MMP13-15, which degrade extracellular molecules (81). We observed elevated expression of transforming growth factor beta-induced protein (TGFBIp) in podocytes treated with GH (81).…”

“…Coincident with the synthesis of ECM components, GH treatment resulted in reduced expression of MMPs, such as MMP7 and MMP13-15, which degrade extracellular molecules (81). We observed elevated expression of transforming growth factor beta-induced protein (TGFBIp) in podocytes treated with GH (81). TGFBIp is also induced by TGF-β and inhibit cell adhesion and interacts with collagen and other matrix structural proteins including integrins.…”

“…Studies from our group demonstrated that mouse podocytes exposed to GH undergo apoptosis (81). A time-dependent increase in the rate of GH-induced apoptosis of mouse podocytes was observed (81).…”