Role of Growth hormone in the Pathogenesis of Podocytopathy and Diabetic Kidney Disease

Kidney development and function rely heavily on growth hormone (GH) and its downstream effector, insulin-like growth factor-I (IGF-I). In type 1 diabetes mellitus (T1DM), elevated GH levels correlate strongly with glomerular injury and proteinuria. Transgenic animal models have further clarified GH's role in diabetic kidney disease (DKD), demonstrating a direct link between elevated GH levels and glomerulosclerosis. Interestingly, because IGF-I transgenic mice escape glomerulosclerosis, evidence suggests a direct pathological contribution by GH itself. Podocytes, which constitute more than 30% of glomerular cells, serve as specialized visceral epithelial cells vital to the permselectivity of the glomerular filtration barrier and maintenance of other glomerular components such as endothelium and mesangium. Since podocytes express the GH receptor (GHR), understanding the direct impact of GH on podocytes is essential to unravel DKD pathology. GH inflicts irreversible podocytopathy by triggering hypertrophy, mitotic catastrophe, and epithelial-mesenchymal transition (EMT), culminating in podocyte loss, glomerulosclerosis, and proteinuria. Mechanistically, these damaging effects are driven by GH-induced ZEB2 expression, reactivation of Notch signaling, and heightened expression of TGF-β1 and TNF-α. Interrupting the GH/GHR cascade, genetically depleting ZEB2, or halting Notch activation effectively prevents this damage, safeguarding both glomerular architecture and overall kidney function. This manuscript provides an overview of aberrations in GH signaling, particularly in T1DM, dissects its cellular and molecular effects on podocytes, and highlights therapeutic approaches to counteract podocytopathy.