Renoprotective effects of a dipeptidyl peptidase 4 inhibitor in a mouse model of progressive renal fibrosis

Abstract

Although the effects of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond their hypoglycemic action have been reported, whether these inhibitors have renoprotective effects in nondiabetic chronic kidney disease (CKD) is unclear. We examined the therapeutic effects of DPP-4 inhibition in mice with unilateral ureteral obstruction (UUO), a nondiabetic model of progressive renal fibrosis. After UUO surgery, mice were administered either the DPP-4 inhibitor alogliptin or a vehicle by oral gavage once a day for 10 days. Physiological parameters, degrees of renal fibrosis and inflammation, and molecules related to renal fibrosis and inflammation were then evaluated using sham-operated mice as controls. Positive area of α-smooth muscle actin was significantly smaller and expression of transforming growth factor β messenger RNA was significantly lower in the alogliptin-treated group than in the vehicle-treated group. Renal total collagen content was also significantly lower in the alogliptin-treated group than in the vehicle-treated group. These results suggest that alogliptin exerted renoprotective antifibrotic effects. The positive area of F4/80 was significantly smaller and expression of CD68 messenger RNA was significantly lower in the alogliptin-treated group than in the vehicle-treated group, suggesting an anti-inflammatory action by the DPP-4 inhibitor. Compared to the results for the vehicle-treated group, expression of markers for M1 macrophages tended to be lower in the alogliptin-treated group, and the relative expression of M2 macrophages tended to be higher. These data indicate the various protective effects of DPP-4 inhibition in nondiabetic mice with UUO. DPP-4 inhibitors may therefore be promising therapeutic choices even for nondiabetic CKD patients.

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

“…These findings support the therapeutic potential of GLP‐1 and adenosine interactions for myocardial infarction and heart failure . In mouse model of renal fibrosis, the expression of PAI‐1 and TGF‐β, as well as interstitial infiltration of macrophages tended to be reduced and tubulointerstitial fibrosis suppressed by alogliptin administered orally 40 mg/kg once daily for 10 days . This gliptin at oral dose of 20 mg/kg daily for 1 week little decreased levels of IL‐1β, ‐6 and reduced macrophages infiltration via GLP‐1‐dependent signaling in the kidney in rat nondiabetic model of glomerular injury …”

“…GLP‐1‐mediated cardioprotection by alogliptin was shown in dogs . This gliptin exerted renoprotective effects in terms of attenuation of inflammation and fibrosis in mice and rats …”

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

“…Since FBs also constitute the center of fibrotic disease etiology in other organs, this finding might have important implications beyond the skin. 1,60 In animal studies, DPP4 + FBs have been shown to be involved in fibrotic pathologies of several other organs, and inhibition of DPP4 activity by gliptins attenuated fibrotic processes in the lung, 61 heart, 62,63 kidney, 64 and liver. 65 Therefore, our transcriptome analysis of DPP4 + FBs in the human skin might represent an important step toward the development of novel anti-fibrotic therapeutic approaches, specifically targeting the DPP4 + FB subset.…”

Effect of dipeptidyl peptidase-4 inhibitors on cisplatin-induced acute nephrotoxicity in cancer patients with diabetes mellitus: A retrospective study

“…Experimentally, DPP-4 inhibitors have been reported to attenuate cisplatin-induced AKI in mice and rats via inhibition of tubular cell death [4,5]. It has also been reported that DPP-4 inhibitors can prevent AKI induced by ischemia-reperfusion and chronic kidney injury in several animal models [6][7][8][9][10]. However, it remains to be investigated whether DPP-4 inhibitors can attenuate kidney injury in human patients.…”