Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease (CKD). In this regard, we recently identified a role for pro-inflammatory Th1 T lymphocyte responses in hypertensive kidney injury. As Th1 cells generate IFN-γ and TNF-α, we hypothesized that IFN-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system (RAS). Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking IFN-γ or TNF-α to our model of hypertensive CKD. IFN-deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (KO) mice had blunted hypertensive responses and reduced end-organ damage in our model. As Ang II-infused TNF KO mice had exaggerated eNOS expression in the kidney and enhanced nitric oxide (NO) bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF KO kidneys into wild-type recipients prior to the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to Ang II and augmented renal eNOS expression, confirming a role for kidney-derived TNF-α to promote Ang II-induced blood pressure elevation by limiting renal NO generation.

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