N-acetyl-seryl-aspartyl-lysyl-proline Inhibits Diabetes-Associated Kidney Fibrosis and Endothelial-Mesenchymal Transition

Abstract

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.

Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice

“…They have been shown to contribute to diabetic cardiomyopathy [29], diabetic nephropathy [30], diabetes-associated kidney fibrosis [31] and diabetic retinopathy [32] through various signal pathways. In the diabetic aorta, EndMTs are part of the calcific vasculopathy.…”

Promoter hypermethylation of let-7a-3 is relevant to its down-expression in diabetic nephropathy by targeting UHRF1

“…was introduced in several diseases, including type 2 DM (Guay and Regazzi, 2013;Natarajan et al, 2012). However, few studies have aimed to define a miRNA expression profile for DN.…”

“…Up-regulation of let-7c could induce fibrosis by suppressing TGF-β1, and the expressions of let-7c targets were dysregulated in human renal fibrosis (Brennan et al, 2013). A study also reported that the expression of let-7 family was suppressed in the diabetic kidney (Nagai et al, 2014). Moreover, our previous study showed that let-7a was down-expressed by microarray in DN patients (J.…”

Pioglitazone Alleviates Cardiac Fibrosis and Inhibits Endothelial to Mesenchymal Transition Induced by Pressure Overload

“…Zeisberg et al verified that EndMT occurs during the progress of cardiac fibrosis in a pressure overload-induced mouse model [4]. Afterwards, they adopted endothelial lineage tracing and observed the emergence of fibroblasts derived from EndMT in the process of kidney fibrosis s [27]. Interestingly, extensive research has attested that TGF-β signaling is potentially involved in the stimulation of EndMT [4, 9, 28].…”