DPP4 inhibition mitigates Ang II-mediated kidney immune activation and injury in male mice.

Recent evidence suggests that DPP4 inhibition with saxagliptin (Saxa) is renoprotective in co-morbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates Ang II-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or angiotensin II (Ang II, 1000ng/kg/min, sc) for 3 weeks receiving either placebo or Saxa (10mg/kg/d, po) during the final 2 weeks. Ang II infusion increased kidney, but not plasma, DPP4 activity <i>in vivo</i> as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with Olmesartan. Further, Ang II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ~50% <i>in vivo</i> and attenuated Ang II-mediated kidney injury, independent of blood pressure. Further mechanistic studies revealed mitigation by Saxa of pro-inflammatory and pro-fibrotic mediators activated by Ang II in the kidney, including CD8+ T cells, resident macrophages (CD11b^hiF4/80^loLy6C-), and neutrophils. In addition, Saxa improved Ang II suppressed anti-inflammatory Treg and Th2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation.