Role Of Vascular Nox5 In Ang Ii-Mediated Pro-Fibrotic And Pro-Inflammatory Signalling In The Kidney

Objective: Mice expressing human Nox5 (hNox5) in vascular smooth muscle cells (VSMC) exhibit increased contraction, ROS generation, cardiac fibrosis and increased pulse pressure. In kidneys, hNox5 in podocytes is associated with albuminuria, hypertension and inflammation. Here we questioned whether VSMC Nox5 influences kidney function and damage in Ang II-induced hypertension. Design and method: Wildtype (WT) and mice expressing hNOX5 in SMC (Nox5+SM22+) were studied. Mice were infused with Ang II (600 ng/Kg/day) for 28 days. Blood pressure was assessed by tail-cuff, kidney damage by histology, and mRNA and protein expression by qPCR and western-blotting, respectively. Inflammatory infiltrate was assessed by FACS. Results: Ang II increased blood pressure (mmHg) in WT (162.7 ± 9) and Nox5+SM22+ (162.3 ± 10). Albuminuria was increased in Nox5+SM22+ versus WT mice (10.2 ± 6 vs 1.27 ± 0.3 mg/mmol, p < 0.05) and by Ang II in both groups (Nox5: 44.8 ± 18; WT: 58.7 ± 12 mg/mmol). Kidneys from Ang II-infused Nox5+SM22+ mice exhibited significant perivascular fibrosis and inflammatory cell infiltration compared to WT. Kidney expression of vimentin (AU: 1.01 ± 0.05 vs WT 0.85 ± 0.03) and aSMA (AU: 0.44 ± 0.03 vs WT 0.33 ± 0.01), markers of myofibroblast differentiation, was increased in Nox5 mice (p < 0.05), an effect that was augmented by Ang II. In kidneys from Nox5+SM22+ mice, levels of macrophage F4/80+ cells were increased (%: 24 ± 2 vs WT 18 ± 1, p < 0.05). Ang II increased macrophage homing in kidneys from WT mice (34 ± 3%, p < 0.05 vs non-treated), but did not further increase it in Nox5 mice (35 ± 5%). Levels of cytotoxic CD8+ T cells and expression of IL-1b and IRAK were increased by Ang II in Nox5 mice. Conclusions: Our study suggests that Nox5 in VSMCs induces renal fibrosis and pro-inflammatory signalling by Ang II, likely through increased ROS generation.