Effects of Dipeptidyl Peptidase-4 Inhibitor and Angiotensin-Converting Enzyme Inhibitor on Experimental Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and worldwide. Proteinuria is a major marker of the severity of injury. Dipeptidyl peptidase-4 inhibitor (DPP-4I) increases incretin-related insulin production and is, therefore, used to treat diabetes. We investigated whether DPP4I could have direct effect on kidney independent of its hypoglycemic activity. We, therefore, tested the effects of DPP4I with or without angiotensin-converting enzyme inhibitor (ACEI) on the progression of diabetic nephropathy and albuminuria in a murine model of DKD. eNOS^-/-db/db mice were randomized to the following groups at age 10 weeks and treated until sacrifice: baseline (sacrificed at week 10), untreated control, ACEI, DPP4I, and combination of DPP4I and ACEI (Combo, sacrificed at week 18). Systemic parameters and urine albumin-creatinine ratio were assessed at baseline, weeks 14, and 18. Kidney morphology, glomerular filtration rate (GFR), WT-1, a marker for differentiated podocytes, podoplanin, a marker of foot process integrity, glomerular collagen IV, and alpha-smooth muscle actin were assessed at the end of the study. All mice had hyperglycemia and proteinuria at study entry at week 10. Untreated control mice had increased albuminuria, progression of glomerular injury, and reduced GFR at week 18 compared with baseline. DPP4I alone reduced blood glucose and kidney DPP-4 activity but failed to protect against kidney injury compared with untreated control. ACEI alone and combination groups showed significantly reduced albuminuria and glomerular injury, and maintained GFR and WT-1⁺ cells. Only the combination group had significantly less glomerular collagen IV deposition and more podoplanin preservation than the untreated control. DPP-4I alone does not decrease the progression of kidney injury in the eNOS^-/-db/db mouse model, suggesting that targeting only hyperglycemia is not an optimal treatment strategy for DKD. Combined DPP-4I with ACEI added more benefit to reducing the glomerular matrix.

Keywords: angiotensin-converting enzyme inhibitor; diabetic kidney disease; dipeptidyl peptidase-4 inhibitor.

Figure 1.. Systemic effects of DPP-4 inhibitor and ACEI in DKD.

A. DPP4I and combination treatment reduced kidney DPP-4 activity. B. DPP4I alone reduced blood glucose levels. C. Body weight was similar among groups. D. ACEI numerically reduced BP, while DPP-4 inhibitor alone increased BP. * p<0.05, ** p<0.01.

Figure 2.. Effects of DPP-4 inhibitor and ACEI on kidney function in DKD.

A. ACEI and combination treatment reduced albuminuria. B. Compared to the untreated control, only combination treatment maintained GFR. * p<0.05, ** p<0.01.

Figure 3.. Effects of DPP-4 inhibitor and ACEI on glomerular injury in DKD.

A. ACEI and combination treatment reduced glomerular injury (PAS, 40X). B. Compared to the untreated control, only combination treatment reduced glomerular collagen IV deposition. * p<0.05, ** p<0.01, *** p<0.001.

Figure 4.. Effects of DPP-4 inhibitor and ACEI on podocytes and mesangial cells in DKD.

A. ACEI and combination treatment maintained WT-1⁺ cell density. B. The combination treatment but not ACEI or DPPI alone effectively preserved glomerular podoplanin levels. C. Compared to the untreated control, only ACEI treatment reduced glomerular α-SMA expression. * p<0.05, ** p<0.01, *** p<0.001.