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.
Highlights
The vertebrate kidney plays an essential role in filtration of blood, regulation of water, electrolyte, and acid-base balance, and thereby maintenance of overall body homeostasis
Identification of growth hormone (GH) receptor (GHR) on podocytes GH induces zinc finger E-box binding homeobox2 expression causes dedifferentiation and detachment of podocytes GH reduces P-cadherin expression and alters podocyte permeability to albumin GH induces transforming growth factor beta induced protein expression and promotes podocyte apoptosis GH transgenic mice showed significant podocyte hypertrophy GH RECEPTOR (GHR) knockout diabetic mice protected from development of Diabetic nephropathy (DN) Loss of binucleated and multinucleated podocytes in urine GH activates mTOR pathway mTOR overactivation recapitulates features of DN
Accumulated evidence suggests a role for the GH/GHR axis in the kidney in DN in type 1 DM (T1DM)
Summary
The vertebrate kidney plays an essential role in filtration of blood, regulation of water, electrolyte, and acid-base balance, and thereby maintenance of overall body homeostasis. The slit pore between neighboring podocytes is 30–50 nm wide [3] This three-layered GFB with a distinct architecture serves as a size-selective and charge-dependent molecular sieve that facilitate the filtration of water, electrolytes, and small solutes while restricting the passage of negatively charged macromolecules including proteins and polypeptides. In the case of overflow proteinuria, low-molecular-weight proteins overwhelm the ability of the proximal tubules to reabsorb proteins from the glomerular ultrafiltrate Most often, this is a result of the immunoglobulin overproduction that occurs in multiple myeloma. Podocytes are vulnerable to various insults during diabetes that result in apoptosis or dedifferentiation Another noticeable feature of podocyte injury is hypertrophy by which podocytes could compensate for the loss of neighboring podocytes.
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