We have previously reported that N-
acetyl-seryl-aspartyl-lysyl-proline (
Ac-SDKP), which is a tetrapeptide hydrolyzed by ACE, inhibits the
transforming growth factor-beta (
TGF-beta)-induced expression of
extracellular matrix proteins via inhibition of the Smad signaling in human mesangial cells. To test in vivo the antifibrotic efficacy of
Ac-SDKP, we examined whether long-term
Ac-SDKP treatment can prevent
renal insufficiency and glomerulosclerosis in diabetic db/db mice. Diabetic db/db mice or nondiabetic db/m mice were treated with
Ac-SDKP for 8 weeks using osmotic minipumps. The treatment with
Ac-SDKP increased plasma
Ac-SDKP concentrations by approximately threefold in both groups but did not affect the
blood glucose levels. Histologically, the increased glomerular surface area, mesangial matrix expansion, and overproduction of
extracellular matrix proteins in db/db mice were significantly inhibited by
Ac-SDKP. Furthermore,
Ac-SDKP treatment normalized the increased plasma
creatinine value in db/db mice, whereas the
albuminuria in
Ac-SDKP-treated db/db mice was somewhat decreased as compared with nontreated db/db mice, although the difference was not statistically significant. In addition, the nuclear translocation of Smad3 was inhibited by
Ac-SDKP. These results demonstrate that long-term
Ac-SDKP treatment ameliorates
renal insufficiency and glomerulosclerosis in db/db mice via inhibition of
TGF-beta/Smad pathway, suggesting that
Ac-SDKP could be useful in the treatment of
diabetic nephropathy.