Abstract
Diabetic kidney disease (DKD) is appeared to be higher risk of declining kidney function compared to non-diabetic kidney disease with same magnitude of albuminuria. Epithelial-mesenchymal transition (EMT) program of tubular epithelial cells (TECs) could be important for the production of the extracellular matrix in the kidney. Caveolin-1 (CAV1), dipeptidyl peptidase-4 (DPP-4) and integrin β1 have shown to be involved in EMT program. Here, we found diabetic kidney is prone for albuminuria-induced TECs damage and DPP-4 plays a vital role in such parenchymal damages in diabetic mice. The bovine serum albumin (BSA) injection induced severe TECs damage and altered expression levels of DPP-4, integrin β1, CAV1, and EMT programs including relevant microRNAs in type 1 diabetic CD-1 mice when compared to non-diabetic mice; teneligliptin (TENE) ameliorated these alterations. TENE suppressed the close proximity among DPP-4, integrin β1 and CAV1 in a culture of HK-2 cells. These findings suggest that DPP-4 inhibition can be relevant for combating proteinuric DKD by targeting the EMT program induced by the crosstalk among DPP-4, integrin β1 and CAV1.
Highlights
Albuminuria is the risk factor for kidney parenchymal damage[1]
We found that CAV1 and either dipeptidyl peptidase-4 (DPP-4) or integrin β1 displayed close proximity as a result of the Transforming growth factor (TGF)-β1 stimulation, while TENE inhibited the proximities of these molecules (Fig.6d–i)
Our research group has focused on the endothelium and reported that Dipeptidyl peptidase (DPP)-4 plays fibrogenic roles by inducing endothelial-mesenchymal transition (EndMT), which is associated with the suppression of anti-fibrogenic miR crosstalk[31,32,33]
Summary
Albuminuria is the risk factor for kidney parenchymal damage[1]. Among the same magnitude of albuminuria stage, patients with diabetic kidney disease (DKD) appear to be higher risk in the progression of declining in kidney function when compared to non-diabetic kidney disease patients[2]. Snail and ZEB1 are zinc-finger transcription factors that are known to bind to the promoter sequence of E-cadherin and induce the EMT program. Twist[1] is a bHLH transcription factor that is known to suppress the expression of E-cadherin and induce the EMT program[8]. Snail, ZEB1 and Twist[1] are relevant for the pathogenesis of kidney damage associated with EMT program. MicroRNA-200 and miR-34 have been shown to regulate the TGF-β-induced EMT program by suppressing the transcription factors ZEB1 and snail[9]. Our group previously reported that the DPP-4 inhibitor linagliptin suppresses the expression of DPP-4 in the kidney by inducing miR-29 and restoring streptozotocin (STZ)-induced kidney fibrosis in CD-1 mice associated with the inhibition of the endothelial-mesenchymal transition (EndMT) and TGF-β/smad[3] signaling[15]. Proteinuria is the significant insult to the kidney and is associated with chronic kidney disease (CKD), such as DN23
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