When Sugar Damages Kidneys: New Hope for Diabetes Patients With Kidney Disease

[okarol]

When Sugar Damages Kidneys: New Hope for Diabetes Patients With Kidney Disease
ScienceDaily (June 15, 2011) — Diabetes mellitus is one of the most common secondary diseases in modern society. And because it is on the rise, it is also one of the greatest challenges facing medicine today. Diabetes patients do not die as a direct result of the increase in blood sugar, but from the long-term complications of their disease, in which the increase in blood sugar causes damage to blood vessels and organs. Kidneys are particularly susceptible to damage, and this can lead to a loss in kidney function and the need to begin a dialysis treatment.
Prof. Dr. Tobias Huber is a kidney expert in the Nephrology Division of the University Medical Center Freiburg. With the support of the Cluster of Excellence BIOSS -- Centre for Biological Signalling Studies, Dr. Huber and his team were able to identify a signalling path that affects the progression of kidney disease in diabetes patients: mTOR is an important metabolic enzyme that controls similar functions in simple organisms, such as yeast and roundworms, as in humans; for example, it controls the growth and reproduction of cells. Diabetes causes the mTOR signalling path to become overactive, which can cause damage in highly specialized kidney cells.
The researchers in Freiburg were able to demonstrate that, although the basal activation of this enzyme may be important for the regular function of renal corpuscles during embryonic development, an overactive mTOR can result in a serious disruption of the kidney filter in diabetes patients and can lead to a total loss of function. In tests on animals, the deliberate genetic interception of this signalling path was able to halt the progression of kidney disease. The results of the research, published in the latest issue of the Journal of Clinical Investigation, offers new possibilities for preventing kidney disease in diabetes patients in the future.
Dr. Huber was also honored last year with the highest scientific award in Germany for kidney research, the Franz Volhard Award, for his achievements in the field of kidney filtration.

http://www.sciencedaily.com/releases/2011/06/110615080221.htm

[greg10]

Thank you for posting.

This topic deserves more than a passing mention.  In this month's issue of JCI (Journal of Clinical Investigation), there were two important and related paper on the molecular mechanism of diabetic nephropathy (DN).  Two groups independently showed how an overactive mTOR regulatory pathway can lead to DN, their abstracts are presented below.  The second group had earlier shown that " systemic administration of rapamycin, a specific and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunctions. Moreover, rapamycin treatment shows a significant reduction in fat deposits and attenuates hyperinsulinemia with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD and that rapamycin could be an effective therapeutic agent for DN.".

Rapamycin, as many transplant patients would know, is an anti-rejection drug first isolated from a bacterium discovered on Easter Island,  It is marketed under the trade name Rapamune by Wyeth.

Clinical trial are also on-going using Rapamycin for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD):
Rapamycin (Rapamune ®, Sirolimus) has been prescribed post-transplant to stop rejection of the new organ.  Everolimus is a biochemically related compound.  Both drugs have been found to inhibit cell growth in cysts by binding to a protein called mTor (mammalian target of rapamycin) in renal cells.  As a result, cyst growth is reduced.



(1) http://www.jci.org/articles/view/44774
Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.


(2) http://www.jci.org/articles/view/44771
Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition–like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.