Ischemic acute kidney injury (AKI) is a major clinical problem with a very high morbidity and mortality rate. Patients with AKI frequently develop remote organ dysfunction including liver and intestinal injury. These extra-renal organ injuries contribute significantly to the overall mortality from AKI. Indeed, most patients who develop AKI do not die due to AKI but succumb from extra-renal complications. Impeding progress for effective therapy, the mechanisms of remote organ injury after ischemic AKI remain obscure. The goal of this proposal is to determine the mechanisms and develop effective treatment for remote organ injury due to ischemic AKI. Recently, we demonstrated that small intestinal Paneth cells play an important role in hepatic and intestinal dysfunction and systemic inflammation after renal ischemia reperfusion (IR) injury in mice. We also demonstrated that Paneth cell-derived IL-17A plays a critical role in generating intestinal and hepatic injury after ischemic AKI. However, the mechanisms that trigger Paneth cell degranulation and dysregulation after renal IR remain obscure. Our long-term goal is to elucidate these mechanisms enabling the development of therapeutic drugs for AKI-induced extra-renal organ dysfunction. Exciting preliminary data generated for this proposal suggest that Toll-like receptor-9 (TLR9) activation may play a role in kidney IR-induced Paneth cell degranulation and IL-17A induction leading to an intestinal inflammatory response and subsequent liver injury. Furthermore, our preliminary data suggest that Paneth cells produce large quantities of norepinephrine in response to IL-17A that further propagates inflammatory response and tissue injury. Finally, preliminary studies suggest that a selective A2b adenosine receptor (AR) agonist induced anti-inflammatory IL-10 generation in Paneth cells and attenuated intestinal and hepatic injury after renal IR. Furthermore, an A2bAR agonist reduced Paneth cell production of IL-17A and norepinephrine after renal IR. Based on these preliminary findings, we hypothesize that ischemic AKI leads to TLR9-mediated Paneth cell degranulation and IL-17A induction leading to Paneth cell-derived norepinephrine synthesis and intestinal and hepatic injury. We will further elucidate the mechanisms and potential therapy for hepatic and intestinal injury after ischemic AKI by testing the following 3 specific aims.
Aim #1 : To determine the mechanisms of Paneth cell dysregulation and degranulation after renal IR.
Aim #2 : To demonstrate that Paneth cells synthesize and release norepinephrine as a major mediator of hepatic and intestinal injury induced by renal IR.
Aim #3 : To develop therapy to reduce AKI induced hepatic and intestinal injury. In summary, our translational proposal aims to provide a novel understanding of the mechanisms of remote organ injury after ischemic AKI. Our proposal also aims to identify novel therapies to reduce systemic complications from ischemic AKI.
Many patients with acute kidney injury die from remote multi-organ dysfunction. In this proposal, we will 1) determine the mechanisms for small intestinal Paneth cell degranulation and IL-17A generation after ischemic AKI, 2) determine whether Paneth cells synthesize and release norepinephrine to propagate intestinal and liver injury after renal IR and 3) develop A2b adenosine receptor and IL-10 based therapies to prevent AKI induced remote organ injury. Overall, our translational proposal is designed to elucidate the mechanisms as well as therapies for remote organ dysfunction after renal ischemia and reperfusion injury.
| Rabadi, May; Kim, Mihwa; Li, Hongmei et al. (2018) ATP induces PAD4 in renal proximal tubule cells via P2X7 receptor activation to exacerbate ischemic AKI. Am J Physiol Renal Physiol 314:F293-F305 |
| Han, Sang Jun; Li, Hongmei; Kim, Mihwa et al. (2018) Kidney Proximal Tubular TLR9 Exacerbates Ischemic Acute Kidney Injury. J Immunol 201:1073-1085 |
| Li, Hongmei; Han, Sang Jun; Kim, Mihwa et al. (2018) Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI. Am J Physiol Renal Physiol 314:F809-F819 |
| Chaudhry, S G; Bentley-Hibbert, S; Stern, J et al. (2018) Growth of liver allografts over time in pediatric transplant recipients. Pediatr Transplant 22: |
