Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury

Abstract

Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

“…Recent study showed that inhibition of CD 26 signaling inhibited human osteoclast development and humanized anti-CD26 monoclonal antibody may have therapeutic potential for the treatment of osteolytic lesions [33]. Recently some studies reported that DPP4i had anti-inflammatory effects and it also becomes the another possibility [34,35]. And increased levels of GIP might be able to affect the result though we did not measure [25,26].…”

The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy

“…In a nondiabetic rat Thy-1 glomerulonephritis model Higashijima et al 28 showed that both alogliptin and anagliptin reduced the number of CD68-positive inflammatory macrophages in the kidney directly via GLP-1-dependent signaling. Because the GLP-1r pathway seems to be less important in the pathogenesis of CKD after 5/6 Nx, we did not see effects on GLP-1r-mediated kidney inflammation as it was reported by Higashijima et al 28 in the Thy-1 glomerulonephritis model. Taken together, anti-inflammatory effects of DPP-4 inhibition seem to be more important in CKD models with a pronounced kidney inflammation.…”

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

“…However, the effect of DPP4 inhibitors in non-diabetic 'proteinuric' kidney diseases is not clear. Recently, Higashijima et al reported that DPP4 inhibitors reduced macrophage infiltration in a rat Thy-1 nephritis model [17].…”