Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff's base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
Edited by Jeffrey E. Pessin Growth hormone (GH) plays a significant role in normal renal function and overactive GH signaling has been implicated in proteinuria in diabetes and acromegaly. Previous results have shown that the glomerular podocytes, which play an essential role in renal filtration, express the GH receptor, suggesting the direct action of GH on these cells. However, the exact mechanism and the downstream pathways by which excess GH leads to diabetic nephropathy is not established. In the present article, using immortalized human podocytes in vitro and a mouse model in vivo, we show that excess GH activates Notch1 signaling in a ␥-secretasedependent manner. Pharmacological inhibition of Notch1 by ␥-secretase inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenyl glycine t-butylester) abrogates GH-induced epithelial to mesenchymal transition (EMT) and is associated with a reduction in podocyte loss. More importantly, our results show that DAPT treatment blocks cytokine release and prevents glomerular fibrosis, all of which are induced by excess GH. Furthermore, DAPT prevented glomerular basement membrane thickening and proteinuria induced by excess GH. Finally, using kidney biopsy sections from people with diabetic nephropathy, we show that Notch signaling is indeed up-regulated in such settings. All these results confirm that excess GH induces Notch1 signaling in podocytes, which contributes to proteinuria through EMT as well as renal fibrosis. Our studies highlight the potential application of ␥-secretase inhibitors as a therapeutic target in people with diabetic nephropathy.
The results indicate an upregulation of αAC, αBC, and Hsp22, but their solubility was compromised in the diabetic retina. There was increased phosphorylation at Ser59, Ser45, and Ser19 of αBC under diabetic conditions. Localization of sHsps and their phosphorylated forms was dispersed to many layers of the retina in diabetes. These results suggest that sHsps may be protecting the retinal neurons in chronic diabetes.
SummaryCataract, loss of eye lens transparency, is the leading cause of blindness worldwide. a-Crystallin, initially known as one of the major structural proteins of the eye lens, is composed of two homologous subunits aA-and aB-crystallins. It is convincingly established now that a-crystallin functions like a chaperone and plays a decisive role in the maintenance of eye lens transparency. The functional ability of a-crystallin subunits is to act in cooperation as molecular chaperones to prevent the cellular aggregation and/or inactivation of client proteins under variety of stress conditions. However, chaperone-like activity of a-crystallin could be deteriorated or lost during aging or under certain clinical conditions because of various genetic and environmental factors. This review will focus specifically on relevance of a-crystallin chaperone function to lens transparency. In particular, we reviewed the studies that demonstrate the modulation of a-crystallin chaperone-like activity and discussed the possibility of chaperone-like activity of a-crystallin as a potential target to prevent or delay the cataractogenesis.2009 IUBMB IUBMB Life, 61(5): [485][486][487][488][489][490][491][492][493][494][495] 2009
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