Insights into the molecular mechanisms leading to kidney dysfunction in diabetic patients

January 12, 2018, Keio University
Insights into the molecular mechanisms leading to kidney dysfunction in diabetic patients
SIRT1 and Claudin-1 levels in kidney biopsies from patients with diabetic nephropathy (DN) and normal kidneys. The results show that SIRT1 levels in PTs and glomerular regions is lower, and Claudin-1 levels in the glomerular region is higher in patients with heavy protein urea compared to those with moderate protein urea. Credit: Keio University

About one-third of diabetes patients suffer from renal failure. Therefore, understanding the mechanisms linking diabetes to renal damage (diabetic nephropathy) would benefit patients as it would help in developing new therapeutic targets and strategies. Sirtuin 1 (Sirt1) is a protein that is involved in cellular stress responses and has been implicated in diabetic nephropathy. However, the exact role of renal Sirt1 on the pathogenesis of renal damage in diabetes has not been fully elucidated.

Researchers in Japan have previously shown that Sirt1 overexpression can alleviate in a Sirt1-overexpressing mouse model. The same group has now established the mechanism that links, at least in part, Sirt1 with the pathogenesis of renal damage in diabetes.

Shu Wakino and colleagues from Keio University, Shizuoka Red Cross Hospital and the Massachusetts Institute of Technology used Sirt1-overexpressing mice, Sirt1 knockout mice and diabetic mouse models to investigate the role of Sirt1 in protecting from diabetes-induced renal damage. Reduction of Sirt1 expression resulted in an increase in Claudin-1 levels and subsequently, albuminuria, which is an early marker of renal damage. The mechanism by which Sirt1 affects the levels of Claudin-1 was found to be through directly epigenetically regulating the expression of the Cldn1 gene. Furthermore, nicotinamide mononucleotide (NMN) was found to mediate the interplay between PTs and podocytes, which are important components of the kidney filtration apparatus, and hence would directly affect albuminuria. Using human renal biopsy samples, the group found that SIRT1 and Claudin-1 levels are also involved in diabetes-related albuminuria in humans.

Taken together the results demonstrate that "Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function," the authors conclude. Furthermore, since observations in patient samples reflect some of the mouse model results the authors state that "the results of this study could contribute to new therapeutic strategies to prevent -induced albuminuria."

Credit: Keio University

Credit: Keio University

Explore further: How berberine works to slow diabetes-related cognitive decline

More information: Kazuhiro Hasegawa et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes, Nature Medicine (2013). DOI: 10.1038/nm.3363

Related Stories

How berberine works to slow diabetes-related cognitive decline

October 31, 2017
Researchers studying the mechanism of action of the natural, plant-derived compound berberine have linked its anti-inflammatory activity and ability to regulate levels of stress-response proteins including sirtuin to berberine ...

No benefit from aliskiren-tied drops in albuminuria

February 1, 2016
(HealthDay)—Reduction in albuminuria with the renin inhibitor aliskiren may be too small to confer clinical benefit in patients with type 2 diabetes, according to a study published online Jan. 13 in Diabetes, Obesity and ...

Macrophage COX-2 prevents diabetic nephropathy progression

November 9, 2016
(HealthDay)—Macrophage cyclooxygenase-2 (COX-2) deletion is associated with progression of diabetic nephropathy (DN), according to an experimental study published online Nov. 4 issue of Diabetes.

How does prostate cancer form?

December 18, 2014
Prostate cancer affects more than 23,000 men this year in the USA however the individual genes that initiate prostate cancer formation are poorly understood. Finding an enzyme that regulates this process could provide excellent ...

Discovery of human genetic mutation could lead to new treatments for type 1 diabetes

March 5, 2013
In type 1 diabetes, the immune system destroys insulin-producing cells in the pancreas, but the precise cause has not been clear. A study published by Cell Press on March 5th in Cell Metabolism reveals that a single mutation ...

Recommended for you

Implantable islet cells come with their own oxygen supply

April 25, 2018
Since the 1960s, researchers have been interested in the possibility of treating type 1 diabetes by transplanting islet cells—the pancreatic cells that are responsible for producing insulin when blood glucose concentration ...

Study shows drug effectiveness in reducing glucocorticoid-induced bone loss

April 25, 2018
About one in every 100 people in the world takes glucocorticoids long term to treat immune-mediated diseases. However, glucocorticoids, such as prednisone, have a side effect—they induce the bone loss called osteoporosis, ...

Bariatric surgery successes lead to type 2 diabetes treatment

April 24, 2018
Bariatric surgery has long yielded almost immediate health benefits for patients with type 2 diabetes, and new findings on the reasons for remission may be the key to developing drug alternatives to surgery.

Hacking human 'drug trafficking' network could make diabetes treatments more effective

April 23, 2018
Making tiny changes to existing diabetes treatments can alter how they interact with cells, and potentially make the medicines more effective.

Vitamin D deficiency linked to greater risk of diabetes

April 19, 2018
An epidemiological study conducted by researchers at University of California San Diego School of Medicine and Seoul National University suggests that persons deficient in vitamin D may be at much greater risk of developing ...

One class of drug used to treat type 2 diabetes may not reduce the risk of death when compared with placebo

April 17, 2018
One class of drug used to treat type 2 diabetes may not reduce the risk of death when compared with placebo, suggests new findings.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.