TA-606

Endothelial-to-mesenchymal transition (EndMT) emerges as an important source of fibroblasts. MicroRNA let-7 exhibits anti-EndMT effects and fibroblast growth factor (FGF) receptor has been shown to be an important in microRNA let-7 expression. The endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a substrate of angiotensin-converting enzyme (ACE). Here, we found that AcSDKP inhibited the EndMT and exhibited fibrotic effects that were associated with FGF receptor-mediated anti-fibrotic program. Conventional ACE inhibitor plus AcSDKP ameliorated kidney fibrosis and inhibited EndMT compared to therapy with the ACE inhibitor alone in diabetic CD-1 mice. The endogenous AcSDKP levels were suppressed in diabetic animals. Cytokines induced cultured endothelial cells into EndMT; coincubation with AcSDKP inhibited EndMT. Expression of microRNA let-7 family was suppressed in the diabetic kidney; antifibrotic and anti-EndMT effects of AcSDKP were associated with the restoration of microRNA let-7 levels. AcSDKP restored diabetes- or cytokines-suppressed FGF receptor expression/phosphorylation into normal levels both in vivo and in vitro. These results suggest that AcSDKP is an endogenous antifibrotic molecule that has the potential to cure diabetic kidney fibrosis via an inhibition of the EndMT associated with the restoration of FGF receptor and microRNA let-7.

Backgrounds: Contrast media (CM)-induced nephropathy (CIN) affects morbidity and mortality in humans.Although CIN is mediated by several factors including the renin-angiotensin system (RAS), little is known about the pathophysiol.To clarify the mechanism, we developed a novel murine CIN model.Methods: We made 5/6 subtotal nephrectomy (NTX) and administered CM (iopamidol) i.v. into the mice 4 wk after NTX.Mice received an angiotensin converting enzyme inhibitor (ACEI, n = 6), an angiotensin II receptor blocker (ARB, n = 4), or ACEI plus a bradykinin B2 receptor antagonist (Hoe-140, n = 5) daily.Results: Serum creatinine levels were significantly elevated in the NTX group compared to the non-NTX group on day 28.A day after CM injection, creatinine levels were addnl. elevated in the non-treated group.While ACEI treatment significantly suppressed the creatinine levels, ARB treatment did not decrease the levels.Hoe-140 negated ACEI's ability to suppress renal dysfunction.Conclusion: ACEI treatment may be useful for the prevention of CM-induced nephropathy.