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 in vivo 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% in vivo 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 (CD11bhiF4/80loLy6C-),
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.