Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat)

Abstract

This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0-2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.

Figure 1

Kidney lipidic peroxidation (MDA) for the lean control and obese diabetic ZDF rats, in the initial and final times (6 weeks of vehicle or 10 mg/kg BW/day sitagliptin treatment). Data is expressed as mean ± sem of 8 rats/group: ***P < 0.001. MDA, malondialdehyde; SITA, sitagliptin.

Figure 2

Evolution of renal lesions with ageing in lean control and obese diabetic ZDF rats: (a) normal renal histology in a lean control rat at 20 weeks of age (PAS, 400x); (b) a glomerulus presenting grade 1 mesangial expansion and thickening of the capsule of Bowman in a lean control rat at 26 weeks of age (PAS, 400x); (c) nodular glomerulosclerosis with sinequia of the tuft to Bowman's capsule, mesangial expansion and arteriolar sclerosis in a diabetic rat of 20 weeks (PAS, 400x); (d) atrophic, sclerosed glomerulus, exhibiting filtrate fluid in Bowman's space. Note the presence of hyaline cylinders and the irregularity of tubular basement membranes, diabetic rat of 26 weeks (PAS, 200x).

Figure 3

Effects of chronic sitagliptin treatment on renal lesions in obese diabetic ZDF rats; (a) regression of glomerulosclerosis, with more glomeruli presenting the more benign nodular form of sclerosis; (b) reduction in capsule of Bowman thickness and absence of sclerosis; (c) although there is persistence of grade 2 capsular thickening, there is absence of sclerosis and only the presence of grade 1 mesangial expansion; (d) presence of light mesangial expansion and hyalinosis of the vascular pole. Note in all figures the absence of hyaline cylinders and a more regular contour of the tubular basement membranes PAS, 400x.

Figure 4

Effects of chronic sitagliptin treatment on renal glomerular and tubulointerstitial lesions in obese diabetic ZDF rats, at the final time (26 weeks). Data is expressed as mean ± sem of 8 rats/group: *P < 0.05 and ***P < 0.001. SITA, sitagliptin.