Toll-like receptor 4 (TLR4) is a molecule involved in innate immune response. Current evidence suggests that activation of TLR4 is associated with vascular and cardiac remodeling by a process which involves production of reactive oxygen species and inflammatory cytokines. Oxidative stress is well established in the development of renal fibrosis in chronic hypertension. In this study, we hypothesized that TLR4 deficiency in C3H/HeJ (C3H) mice protects the kidney from angiotensin induced renal remodeling by reducing mitochondrial oxidative stress. Wildtype (WT) and C3H mice were implanted with osmotic pumps loaded without or with Angiotensin-II (Ang-II) for delivery at 250 ng/kg/min for 4 weeks. Animal groups were 1) WT + Saline, 2) WT + Ang-II, 3) C3H + Saline, 4)
C3H + Ang-II. Blood pressure was measured weekly and end-point laser Doppler flowmetry was done to assess renal cortical blood flow. Superoxide content was measured by dihydroethidium staining. Mitochondrial oxidative stress was measured by H2O2 production, manganese superoxide dismutase (MnSOD) and catalase was measured by gel and assay method respectively. Ang-II administration induced higher blood pressure in WT mice than in C3H mice (135.8 ± 5.1 vs. 109.4 ± 5.6 mm of Hg). Ang-II decreased renal cortical flux to a greater degree in WT mice compared to C3H mice [1052.8 ± 67.8 vs. 1182.9 ± 24.7 perfusion units (PU)]. Superoxide content was increased in WT + Ang-II mice compared to C3H + Ang-II. The expression and activity of mitochondrial MnSOD was increased in C3H mice compared to WT mice receiving Ang-II. H2O2 production was increased in C3H + Ang-II compared to WT mice receiving similar treatment. Collagen accumulation and wall-to-lumen ratio was increased in the cortical vessels of WT mice compared to C3H mice receiving Ang-II indicating fibrosis. C3H mice also exhibited lower levels of inflammatory cytokines TGF-β, TNF-α and IL-6 than WT mice receiving Ang-II. Our data suggests that in TLR4 deficiency (C3H mice), upregulation of mitochondrial MnSOD reduces reactive oxygen species production and inflammation and thus renovascular remodeling in Ang-II induced hypertension.