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

Abstract

The kidney regulates water, electrolyte, and acid-base balance and thus maintains body homeostasis. The kidney's potential to ensure ultrafiltered and almost protein-free urine is compromised in various metabolic and hormonal disorders such as diabetes mellitus (DM). Diabetic nephropathy (DN) accounts for ~20-40% of mortality in DM. Proteinuria, a hallmark of renal glomerular diseases, indicates injury to the glomerular filtration barrier (GFB). The GFB is composed of glomerular endothelium, basement membrane, and podocytes. Podocytes are terminally differentiated epithelial cells with limited ability to replicate. Podocyte shape and number are both critical for the integrity and function of the GFB. Podocytes are vulnerable to various noxious stimuli prevalent in a diabetic milieu that could provoke podocytes to undergo changes to their unique architecture and function. Effacement of podocyte foot process is a typical morphological alteration associated with proteinuria. The dedifferentiation of podocytes from epithelial-to-mesenchymal phenotype and consequential loss results in proteinuria. Poorly controlled type 1 DM is associated with elevated levels of circulating growth hormone (GH), which is implicated in the pathophysiology of various diabetic complications including DN. Recent studies demonstrate that functional GH receptors are expressed in podocytes and that GH may exert detrimental effects on the podocyte. In this review, we summarize recent advances that shed light on actions of GH on the podocyte that could play a role in the pathogenesis of DN.

Keywords: dedifferentiation; diabetic nephropathy; growth hormone; hypertrophy; podocytes; zinc finger E-box binding homeobox2.

Figure 1

(A) Cartoon depicting the organization of nephron, glomerulus, and glomerular filtration barrier. The glomerular filtration barrier (GFB) comprises endothelial cells (ECs) of glomerular capillaries, basement membrane (BM), and podocytes (PC). Podocytes are specialized glomerular epithelial cells and slit diaphragm (SD) forms a contact between them and contributes to the glomerular permselectivity. (B) The natural course of diabetic nephropathy (DN). Progression of DN is associated with progressive proteinuria from micro albuminuria to overt proteinuria. The course of DN is also associated with histological manifestations in the glomerulus such as hypertrophy of podocytes, widening of glomerular BM, glomerulosclerosis, and depletion of podocytes, and these events culminate in end-stage renal disease.

Figure 2

GH acts via a variety of signal transduction pathways. Multiple GH signaling pathways can contribute to specific GH responses. GH binds to GHR and activates JAK2 that in turn triggers an array of signaling cascade. These interconnected signal transduction pathways regulate various metabolic and cellular events. GH, growth hormone; GHR, growth hormone receptor; JAK2, Janus kinase 2; IRS, insulin receptor substrate; PI3K, phosphatidyl inositol 3-kinase; STAT, signal transducer and activator of transcription; Grb2-SOS, growth factor receptor-bound 2-son of sevenless complex; FAK, focal adhesion kinase; SH2-Bβ, src-homology 2 domain Bβ; MAPK, mitogen-activated protein kinase.

Figure 3

Growth hormone (GH)–GH receptor (GHR)–IGF-1 axis in type 1 diabetes. Pituitary GH acts via GHR and induces hepatic insulin-like growth factor (IGF-1) production, which serves as a surrogate marker for GH action (1). However, in type 1 diabetes, reduced portal insulin levels results in decreased expression of hepatic GHR, impaired IGF-1 production and elevated IGFBP-1 levels (2). Low bioavailability of IGF-1 leads to compensatory GH hypersecretion via negative feedback loop mechanism (3). Except in liver, GHR expression in other tissues including kidney is not compromised. Elevated GH levels in poorly controlled type 1 diabetes associated with elevated GHR and IGF-1 in the kidney (4). Elevated GH levels are implicated in the renal hyperfiltration, glomerulosclerosis, nephromegaly, and proteinuria (5).

Figure 4

Proposed model for the growth hormone (GH) action on glomerular podocyte. GH-induced cellular events in podocyte include dedifferentiation of podocytes or thickening and/or cross-linking of the basement membrane. Both these events result in the shedding of podocytes. Alternatively, GH induces podocyte apoptosis and hypertrophy. All these changes in podocytes manifest in decreased podocyte count and impair glomerular function in pathological states of overactivity of GH/GH receptor axis such as acromegaly and type 1 diabetes.