The World Health Organization estimates that hypertension impacts 40% of the world?s adult population. Despite the catastrophic cardiovascular complications of hypertension such as stroke, congestive heart failure, and chronic kidney disease (CKD), blood pressure remains poorly controlled in more than half of patients carrying the diagnosis 7. The SPRINT trial demonstrated the benefits of tight blood pressure control, highlighting the need to develop novel agents to further reduce blood pressure and limit target organ damage in hypertension. The recent recognition that innate immune responses contribute to hypertension and its complications should facilitate the development of novel immunomodulatory interventions for hypertension. However, disrupting the pro-hypertensive actions of inflammatory mediators without inducing harmful immunosuppression will require elucidation of the discrete cell-specific mechanisms through which innate immune responses drive blood pressure elevation and consequent end organ injury. Circulating monocytes and tissue macrophages are key effectors of innate immunity, and interleukin-1 (IL-1) is the prototypical cytokine produced by pro-inflammatory macrophages. We have found in a murine hypertension model that genetic deletion or pharmacologic blockade of the receptor for IL-1 (IL-1R1) enhances urinary excretion of nitric oxide (NO), attenuates renal sodium retention, inhibits the NKCC2 transporter, and limits blood pressure elevation. We therefore hypothesize that IL-1 receptor activation on kidney epithelial cells suppresses their generation of NO and thereby promotes sodium reabsorption in the nephron. To test this hypothesis, we will examine renal sodium transport, NO generation, and susceptibility to hypertension in a murine model of nephron-specific IL-1R1 deficiency (IL-1R KKO). Treating these animals with angiotension receptor blockade (ARB) and diuretics will identify additive clinical benefits of abrogating IL-1R1 signals in kidney epithelial cells and elucidate downstream mechanisms through which the IL-1R in the nephron raises blood pressure. Uncontrolled hypertension and other causes of CKD culminate in irreversible kidney fibrosis. NO can also attenuate renal fibrosis, and our new preliminary data suggest that myeloid cell-specific deletion of IL-1R mitigates ischemic damage that drives renal fibrogenesis. We therefore posit that IL-1R1 activation in intra-renal macrophages attenuates their generation of NO and exacerbates kidney fibrosis. We will directly test the contribution of IL-1R1 in macrophages to kidney fibrogenesis by genetically excising IL-1R1 from myeloid cells in mice (IL-1R KKO) and subjecting these animals to insults that trigger renal fibrosis. With this stepwise approach, we will discover complementary, cell-specific actions of IL-1R1-dependent blood pressure regulation and kidney damage that can underpin the development of novel immunomodulatory therapies for hypertension.
Hypertension impacts 30% of adults in the United States and leads to severe cardiovascular complications including stroke, congestive heart failure, and end-stage kidney disease. The current proposal will elucidate mechanisms through which myeloid cells interact with kidney tubular cells to regulate salt transport in the kidney during hypertension and provoke inflammation leading to renal scar formation. Knowledge of these mechanisms will allow the design of potent immune-directed therapies to more effectively lower blood pressure and limit target organ damage in hypertension.
