Abstract P475: What’s in a Letter: N vs. J Determines Responses to Ang II/DOCA and DPP4 Gene Deletion

Abstract

Activation of the renin-angiotensin-aldosterone system (RAAS) drives blood pressure (BP) responses and kidney injury in humans and rodent models. Previously, we reported activation of dipeptidyl peptidase 4 (DPP4) by RAAS which may play an important role in BP responses and kidney injury. Classically, either angiotensin II (Ang II) or deoxycorticosterone (DOCA)-salt administration to mice, raises their BP over a period of hours to days. Recently, the two have been combined to elicit more robust kidney injury and proteinuria. Although there are not many head to head comparison studies, it is known through historical association that different strains of mice have different baseline BPs and vary in their response to vasoconstrictor agents for BP peaks as well as associated kidney injury. In this regard, the C57Bl/6J and C57Bl/6N mice are genetically very similar although they differ with respect to their responses to circadian rhythm on salt sensitivity to BP. Therefore, we hypothesized that J versus N strain will have differential BP responses to Ang II/DOCA and kidney injury susceptibility. C57Bl/6 J and N mice ( DPP4 +/+ and DPP4 -/- ) were subjected to Ang II/DOCA salt infusion for 2 weeks (Ang II 1000ng/kg/min via miniosmotic pumps, DOCA 50mg pellet, 0.9% saline in drinking water) and compared to mice receiving saline only (osmotic pumps). BP was measured by Millar catheter. Kidney injury was quantified via albuminuria and histology. While the Ang II/DOCA treated J strain had mean BP (MBP) of 135mmHg, the Ang II/DOCA treated N strain had MBP of 125mmHg. There was no effect of DPP4 gene deletion on BP in either strain. The J strain treated with Ang II/DOCA salt had higher albuminuria when compared to the N strain (180ug/ml vs. 60ug/ml). DPP4 -/- mice on the J strain receiving Ang II/DOCA had a relative improvement in albuminuria (120ug/ml vs. 180ug/ml). Surprisingly, the DPP4 -/- mice on the N strain had higher albuminuria when compared to the DPP4 +/+ mice receiving Ang II/DOCA (143ug/ml vs. 60ug/ml). Taken together, our results suggest that mice strain plays an important role in BP and kidney injury responses to Ang II/DOCA and DPP4 gene deletion. These results highlight the importance of selecting patient populations carefully to maximize the benefit of DPP4 inhibitors.