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NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db/db mice
Li Zhang1, Ruizhao Li, Wei Shi
1Southern Medical University, Guangzhou, China; Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Background And Purpose:
Podocyte injury plays a key role in the development of diabetic nephropathy (DN). We have recently shown that 11R-VIVIT, an inhibitor of cell-permeable nuclear factor of activated T-cells (NFAT), attenuates podocyte apoptosis induced by high glucose in vitro. However, it is not known whether 11R-VIVIT has a protective effect on DN, especially podocyte injury, under in vivo diabetic conditions. Hence, we examined the renoprotective effects of 11R-VIVIT in diabetic db/db mice and the possible mechanisms underlying its protective effects on podocyte injury in vivo and in vitro.
Experimental Approach:
Type 2 diabetic db/db mice received i.p. injections of 11R-VIVIT (1 mg·kg(-1)) three times a week and were killed after 8 weeks. Immortalized mouse podocytes were cultured under different experimental conditions.
Key Results:
11R-VIVIT treatment markedly attenuated the albuminuria in diabetic db/db mice and also alleviated mesangial matrix expansion and podocyte injury. However, body weight, food and water intake, and glucose levels were unaffected. It also attenuated the increased NFAT2 activation and enhanced urokinase-type plasminogen activator receptor (uPA receptor) expression in glomerulor podocytes. In cultured podocytes, the increased nuclear accumulation of NFAT2 and uPA receptor expression induced by high glucose treatment was prevented by 11R-VIVIT or NFAT2-knockdown; this was accompanied by improvements in the filtration barrier function of the podocyte monolayer.
Conclusions And Implications:
The NFAT inhibitor 11R-VIVIT might be a useful therapeutic strategy for protecting podocytes and treating DN. The calcinerin/NFAT2/uPA receptor signalling pathway should be exploited as a therapeutic target for protecting podocytes from injury in DN.
Insights
The nuclear factor of activated T-cells (NFAT) inhibitor 11R-VIVIT protects against diabetic nephropathy (DN) by preventing podocyte injury. This study shows 11R-VIVIT is a potential therapeutic strategy for DN treatment.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Diabetic nephropathy (DN) involves significant podocyte injury.
- Nuclear factor of activated T-cells (NFAT) inhibition shows promise in vitro for podocyte protection.
- The in vivo efficacy of NFAT inhibitors in DN remains largely unexplored.
Purpose of the Study:
- To investigate the renoprotective effects of 11R-VIVIT in a mouse model of type 2 diabetes.
- To elucidate the mechanisms by which 11R-VIVIT protects podocytes in vivo and in vitro.
Main Methods:
- Diabetic db/db mice received 11R-VIVIT injections for 8 weeks.
- In vitro studies utilized cultured immortalized mouse podocytes under high glucose conditions.
- Assessed albuminuria, kidney pathology, NFAT2 activation, and urokinase-type plasminogen activator receptor (uPA receptor) expression.
Main Results:
- 11R-VIVIT treatment reduced albuminuria and mesangial matrix expansion in diabetic mice.
- Podocyte injury was alleviated without affecting body weight or glucose levels.
- 11R-VIVIT inhibited NFAT2 activation and uPA receptor expression in podocytes, improving filtration barrier function.
Conclusions:
- 11R-VIVIT demonstrates therapeutic potential for protecting podocytes and treating diabetic nephropathy.
- The calcineurin/NFAT2/uPA receptor pathway represents a viable therapeutic target for DN-related podocyte injury.
