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.

Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytes

“…Primary hallmarks of DN are podocyte dedifferentiation, hypertrophy, maladaptive proliferation, and apoptosis (17). Podocytes are particularly vulnerable to the noxious stimuli of diabetic milieu (18,19), and, since they cannot proliferate, podocyte damage and loss result in the impairment of the integrity and function of the glomerular filtering barrier and the subsequent loss of proteins into the urine (17). In response to the various stressful stimuli (including high glucose, free radicals, mechanical stress), podocytes reenter the cell cycle, increase in size, and frequently undergo mitosis with nuclear division but do not complete cytokinesis (20,21), generating aneuploid podocytes.…”

Structural Features and Oligomeric Nature of Human Podocin Domain

“…The SD is a negatively charged zipper-like structure bridging the 30-40nm gap between the adjacent foot processes. This structure curbs the passage of albumin and other large molecules from the blood into primary urine thereby tightly regulating the composition of the glomerular filtrate [3,4]. The intricate structure of the SD is maintained by an array of protein assemblies.…”

“…DLS analysis of the samples corresponding to peak observed in SEC-MALS (1-5) is represented as a number percentage vs size in nanometers curve plots marked in different colors (A-E). The corresponding correlograms of the samples(1)(2)(3)(4)(5) represented as correlation coefficient vs time in microseconds.…”

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

“…Injury to the podocytes including hypertrophy, foot process effacement, and epithelialmesenchymal-transition (EMT) results in reduced podocyte count [2]. Podocyte loss leaves GBM denuded and provokes neighboring podocytes to undergo compensatory hypertrophy.However, the molecular signals that initiate the podocyte or glomerular hypertrophy remains unclear.Elevated growth hormone (GH) levels in poorly controlled type 1 diabetes mellitus (DM) is implicated as a causative factor in the development of renal aberrations and proteinuria [2][3][4].GH transgenic animals developed significant renal hypertrophy and glomerulosclerosis [5].Albeit, part of the biological effects of GH are mediated by insulin-like growth factor 1 (IGF-1), the glomerular hypertrophy and significant renal manifestations are evidenced in GH transgenics with IGF-1 null background suggesting that GH, but not IGF-1 responsible for glomerular hypertrophy [6]. In GH transgenic animals, podocytes undergo hypertrophy while mesangial and endothelial cells undergo proliferation [6].…”

“…Elevated growth hormone (GH) levels in poorly controlled type 1 diabetes mellitus (DM) is implicated as a causative factor in the development of renal aberrations and proteinuria [2][3][4].…”