Tumor Necrosis Factor-α Produced in the Kidney Contributes to Angiotensin II–dependent Hypertension

Abstract

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.

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells

“…TNFα [50], IL-1β [51] and other circulating PIC [51,52] have been reported to increase in the kidney with the severity of hypertension. However, the mechanisms by which hypertension contributes to the progression of renal injury is not clear.…”

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

“…These findings are in agreement with several previous studies indicating that NO in general, and NOS3 in particular, inhibits thick ascending limb NKCC2. As mentioned earlier, NO, via cGMP, inhibits NKCC2 activity in isolated thick ascending limb1, 2; thick ascending limb NO production, whether agonist‐modulated (ET‐1, angiotensin‐II, or inflammatory cytokines)12, 25, 26 or in disease states (diabetes mellitus and Dahl salt‐sensitive hypertension27, 28) derives, at least in part, from NOS3.…”

“…Beyond their physiological relevance, these findings are particularly important considering the findings that NOS3/NO regulation of NKCC2 may partly account for genetic salt‐sensitive hypertension (Dahl S versus Dahl R rats),33 angiotensin II‐induced hypertension12, 25, 26 and diabetes mellitus‐associated hypertension 27. Further, these findings suggest that NOS3‐derived NO in the distal tubule may be important in BP regulation in health and disease, a heretofore unexplored area.…”

TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function

“…2007), and that hypertension was blunted in 2‐ to 3‐week Ang‐II‐infused TNF‐deficient mice (Zhang et al. 2014a; Sriramula and Francis 2015). Other studies using TNFR1‐KO mice described an even greater hypertensive response to Ang‐II infusion than WT mice (Chen et al.…”