The glomerular podocyte as a target of growth hormone action: implications for the pathogenesis of diabetic nephropathy

Abstract

Involvement of the growth hormone (GH) / insulin-like growth factor 1 (IGF-I) axis in the pathogenesis of diabetic nephropathy (DN) is strongly suggested by studies investigating the impact of GH excess and deficiency on renal structure and function. GH excess in both the human (acromegaly) and in transgenic animal models is characterized by significant structural and functional changes in the kidney. In the human a direct relationship has been noted between the activity of the GH/IGF-1 axis and renal hypertrophy, microalbuminuria, and glomerulosclerosis. Conversely, states of GH deficiency or deficiency or inhibition of GH receptor (GHR) activity confer a protective effect against DN. The glomerular podocyte plays a central and critical role in the structural and functional integrity of the glomerular filtration barrier and maintenance of normal renal function. Recent studies have revealed that the glomerular podocyte is a target of GH action and that GH's actions on the podocyte could be detrimental to the structure and function of the podocyte. These results provide a novel mechanism for GH's role in the pathogenesis of DN and offer the possibility of targeting the GH/IGF-1 axis for the prevention and treatment of DN.

Fig 1. Role of the GH/IGF-1 axis in the pathogenesis of diabetic nephropathy

Poorly controlled Type 1 diabetes mellitus is characterized by decreased GHR expression and activity in the liver⁽¹⁾ and consequent decrease in hepatic IGF-1 production⁽²⁾. Low circulating levels IGF-1 levels stimulate increased pituitary GH secretion⁽³⁾ via negative feed back loop mechanisms. In contrast to the liver, in the kidney GHR⁽⁵⁾ expression is maintained (or increased) and hence the kidney is exposed to the effects of the elevated levels of GH⁽⁴⁾ in the circulation. One of the cell types that is a direct target for GH action in the kidney is the glomerular podocyte. GH’s actions on the podocytes include modulation of levels of proteins such as SIP1 and E-cadherin that in concert with actions of IGF-1 could play a role in the pathogenesis of proteinuria and other changes characteristic of diabetic nephropathy.