Effect of Antifibrotic MicroRNAs Crosstalk on the Action of N-acetyl-seryl-aspartyl-lysyl-proline in Diabetes-related Kidney Fibrosis

Abstract

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous antifibrotic peptide. We found that suppression of AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of antifibrotic microRNA (miR)s in kidneys, were imperative to understand the mechanisms of fibrosis in the diabetic kidneys. Analyzing streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing AcSDKP and antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4 protein expression/activity and endothelial to mesenchymal transition. In diabetic CD-1 mice, these alterations were all reversed by AcSDKP treatment. Transfection studies in culture endothelial cells demonstrated crosstalk regulation of miR-29s and miR-let-7s against mesenchymal activation program; such bidirectional regulation could play an essential role in maintaining the antifibrotic program of AcSDKP. Finally, we observed that AcSDKP suppression in fibrotic mice was associated with induction of both interferon-γ and transforming growth factor-β signaling, crucial molecular pathways that disrupt antifibrotic miRs crosstalk. The present study provides insight into the physiologically relevant antifibrotic actions of AcSDKP via antifibrotic miRs; restoring such antifibrotic programs could demonstrate potential utility in combating kidney fibrosis in diabetes.

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

“…Indeed, we have shown that DPP-4 suppression in endothelial cells represses TGFb2-induced EndMT (30)(31)(32). Such effects of DPP-4 inhibition are thought to associate with the induction of antifibrotic miRs such as let-7 and miR-29, which have been shown to inhibit TGFb signaling (33). In contrast, surprisingly, our findings revealed that DPP-4 suppression is sufficient to induce EMT and cell migration in normal mammary epithelial cells and cancer cells.…”

Novel Anti-fibrotic Therapies

“…Multiple works have defined the role of miRNAs in renal fibrosis including the effects of miR-148b and members of the miR-29 and miR-let7 families (Fang et al, 2013; Nagai et al, 2014; Szeto and Li, 2014; Srivastava et al, 2016). Additionally, recent studies have demonstrated functional advancements as protection from fibrosis was gained from anti-miR-214 treatment (Denby et al, 2014).…”

The pathological significance of dipeptidyl peptidase-4 in endothelial cell homeostasis and kidney fibrosis

“…Importantly, miR-29 also targets integrin b1 [80,81]; therefore, the levels of miR-29s can directly affect the levels of both DPP-4 and integrin b1. Furthermore, very recently, we have shown [82] that miR-29s and miR-let-7s, another miR, play anti-EndMT roles [83] consisting of anti-EndMT crosstalk regulation against the mesenchymal activation program in vivo and in vitro. This type of bidirectional regulation between two miRs could play an essential role in maintaining the anti-EndMT program [82].…”

“…Furthermore, very recently, we have shown [82] that miR-29s and miR-let-7s, another miR, play anti-EndMT roles [83] consisting of anti-EndMT crosstalk regulation against the mesenchymal activation program in vivo and in vitro. This type of bidirectional regulation between two miRs could play an essential role in maintaining the anti-EndMT program [82]. Therefore, DPP-4-inhibition-associated induction of miR-29s can be relevant to the suppression of EndMT programs via the suppression of miR-29 target genes such as DPP-4 and integrin b1, as well as the induction of anti-EndMT miRs crosstalk.…”