Human growth hormone-induced mitotic maladaptation in podocytes and implications in diabetic kidney disease

Diabetes is a significant risk factor for the development of diabetic kidney disease, and about 30% of people with type I diabetes mellitus will eventually develop end-stage kidney disease. Growth hormone (GH) and its mediator insulin-like growth factor (IGF-I) are crucial for kidney development and function in healthy conditions. However, elevated circulatory levels of GH in type I diabetes mellitus disrupt homeostasis and cause changes in the kidney's structure and function, such as hypertrophy, glomerulosclerosis, and proteinuria. Glomerular podocytes are specialized cells in the nephron, and they practically represent the kidney's filtration function. Podocytes are terminally differentiated cells, and podocyte injury or loss causes significant damage to the glomerulus manifested by varying degrees of proteinuria. Recent studies have identified that podocytes express GH receptors and are key targets of GH action, particularly in settings with type I diabetes mellitus. GH could negatively affect podocyte biology, thus potentially contributing to glomerular manifestations, kidney damage, and thereby contribute to diabetic kidney disease. GH evokes the reactivation of the embryologically active Notch signaling in adult podocytes. As a consequence, terminally differentiated podocytes undergo cell-cycle reentry. This manuscript overviews the aberrant activation of embryologically active pathways in quiescent adult podocytes, complications of cell-cycle reentry, aberrations in cytokinesis, and consequent mitosis-associated cell death.