N-
acetyl-seryl-aspartyl-lysyl-proline (
Ac-SDKP), which is hydrolyzed by
angiotensin-converting enzyme, is a natural regulator of hematopoiesis. Here it is shown that
Ac-SDKP inhibits
TGF-beta action in mesangial cells. Because
TGF-beta is thought to play a pivotal role in the development and progression of
glomerulonephritis, the
therapeutic effects of
Ac-SDKP on an established model of renal dysfunction and histologic alteration in Wistar-Kyoto rats with anti-glomerular basement membrane
nephritis was examined. Fourteen days after the induction of anti-glomerular basement membrane
nephritis, the rats were treated subcutaneously with
Ac-SDKP at a dose of 1 mg/kg per d for 4 wk. Treatment with
Ac-SDKP significantly improved
proteinuria and renal dysfunction, including increased plasma blood
urea nitrogen and
creatinine levels and decreased
creatinine clearance. Histologic examination showed severe glomerulosclerosis and interstitial
fibrosis in the vehicle-treated rats, whereas these histologic
injuries were significantly ameliorated in rats that were treated with
Ac-SDKP. The histologic improvements were accompanied by the suppression of gene and
protein expression of
fibronectin, interstitial
collagen, and
TGF-beta1 in the nephritic kidney. Furthermore, treatment with
Ac-SDKP resulted in the inhibition of Smad2 phosphorylation, an increase in Smad7 expression in the kidney, and reduction of macrophage accumulation into the glomeruli and tubulointerstitium in nephritic rats. In conclusion,
Ac-SDKP significantly ameliorated the progression of renal dysfunction and
fibrosis even after the establishment of
nephritis. The inhibitory effect of
Ac-SDKP was mediated in part by the inhibition of
TGF-beta/Smad signal transduction and the inflammatory response. These findings suggest that
Ac-SDKP treatment may be a novel and useful therapeutic strategy for the treatment of progressive renal diseases.