Dysfunctional Renin-Angiotensin System in Septic Shock

Scientific Abstract: Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite best therapy efforts. Circulating markers of septic shock severity may constitute a clinically relevant approach to individualize therapy and resuscitation for those patients at risk for poor outcomes early in the course of the disease, which may facilitate early and more precise intervention to improve patient outcomes. However, currently used septic shock biomarkers including lactate, may be non-specific, and have variable impacts on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is an early event in septic shock and recent data has shown that elevated renin, is more predictive of worse outcomes in septic shock than lactate, as well as a more relevant biomarker for mortality. However, our preliminary data suggest that activation of the RAAS downstream from renin, particularly the Angiotensin Converting Enzyme (ACE)- Angiotensin II (Ang II)-AT1 receptor axis is blunted, thus contributing to the severity of septic shock through a reduced ability to maintain adequate blood pressure and tissue perfusion, as well as an attenuated immune response. The current project proposes a randomized clinical trial to precisely determine the benefit of exogenous Ang II versus norepinephrine (conventional care) treatment in septic shock patients. Moreover, we will determine whether there are more precise and complete measures of renin and other RAAS components (prorenin, aldosterone, Angiotensinogen (Aogen), DPP3, ACE, ACE2 and Ang II) that provide stronger associations and better predictors of septic shock severity. This approach may inform more appropriate treatment regimens and improve outcomes for these patients. Specifically, Aim 1 proposes a clinical trial to compare the benefits of Ang II treatment and the norepinephrine (NE). Aim 2 will assess protein levels of renin, prorenin, aldosterone, Ang II, Aogen (total and intact), DPP3 and ACE, as well as their ratios in comparison to serum lactate as the strongest predictor of disease severity and outcomes in septic shock patients prior to and following Ang II and NE treatment. Aim 2 also establishes the regulation of Aogen by serum factors from septic shock patients prior to and following Ang II and NE treatment. Aim 3 will assess the response of the immune system regarding monocyte function and cell signaling events associated with the RAAS in the septic shock before and after treatment. Successful accomplishment of our aims will provide the capability to improve endotyping of septic patients by establishing the most precise and robust measurement of renin (and RAAS dysfunction). This work will improve staging and clinical precision and will facilitate the criteria for therapeutic development of targets in septic shock. Project Number: 1R01HL177834-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: MARK CHAPPELL (+1 co-PI) | Institution: WAKE FOREST UNIVERSITY HEALTH SCIENCES, WINSTON-SALEM, NC | Award Amount: $753,208 | Activity Code: R01 | Study Section: Surgery, Anesthesiology and Trauma Study Section[SAT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17783401