Abstract 059: Kidney Specific DPP4 Knockdown Prevents Ang II/DOCA Salt Injury and Proteinuria

Abstract

Dipeptidyl peptidase 4 (DPP4) inhibition is widely used for glycemic control in type 2 diabetes mellitus (T2DM) subjects. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial showed that DPP4 inhibition improves proteinuria in type 2 DM (T2DM) subjects with chronic kidney disease (CKD). Our lab and others have observed that kidney DPP4 activation is associated with proteinuria in conditions of RAAS activation including obesity. However, it is not clear if kidney specific DPP4 directly plays a role in kidney injury. To test our hypothesis, right nephrectomy (UNx) mice were subjected to 1) sham surgery 2) left renal vein injection with lentivirus carrying DPP4 shRNA (UNx+DPP4) 3) scramble shRNA (UNx+SCRM) and the animals were allowed to recover for 2-3 wks. A 4 th group of non-UNx mice were added as additional controls. Next, angiotensin II (Ang II, 1000ng/kg/min) plus deoxycorticosterone (DOCA, 50mg) plus 0.9% NaCl (salt) or saline only was given for 2 wks. Ang II/DOCA salt caused heart hypertrophy in all groups when compared to saline infusion (p<0.05). DPP4 knockdown reduced albuminuria (UNx+Ang II/DOCA salt, 80.18±15.3 ug/mg Crt; UNx+DPP4+Ang II/DOCA salt, 25.76±19.3 ug/mg Crt; UNx+SCRM+Ang II/DOCA salt 100.1±17.6 ug/mg Crt, p<0.05). Flow cytometry analysis showed that DPP4 knockdown mitigated activation of CD4+ T cells by Ang II/DOCA salt as indicated by reduced surface expression of DPP4 on CD4+, CD44+CD127+ central memory and CD44+CD127- effector cells. In addition, DPP4 knockdown prevented Ang II/DOCA salt-mediated infiltration of Ly6ChiCD11bhiF4/80lo macrophages and decreased the Ly6C-CD11bloF4/80hi resident dendritic cells. DPP4 knockdown suppressed Ang II/DOCA salt mediated activation of pro-fibrotic markers, Col1A and CTGF. Lastly, DPP4 knockdown suppressed glomerulomegaly, mesangial expansion and interstitial inflammation on trichrome stain. In summary, RAAS activation is a prominent mechanism for kidney injury in T2DM and obese subjects. Kidney DPP4 is an important effector of RAAS mediated kidney inflammation, activation of pro-fibrotic markers and proteinuria, thereby implicating DPP4 in CKD initiation and progression.