NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db/db mice.

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. [ABSTRACT FROM AUTHOR]

Copyright of British Journal of Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)