#2837 ANGIOTENSIN II TYPE 1A RECEPTOR IN KIDNEY PERICYTES MEDIATES TERTIARY LYMPHOID TISSUE FORMATION AFTER ACUTE KIDNEY INJURY

Abstract

Abstract Background and Aims Tertiary lymphoid tissues (TLTs) have been demonstrated as a major cause of sustained inflammation after acute kidney injury (AKI), indicating a possible contribution of ensuing chronic kidney disease (CKD). And heterogeneous fibroblasts play the crucial role of induction of TLT by secretion of chemokines. Angiotensin II receptors also express on fibroblasts including pericytes. Our study aimed to investigate whether the blockade of angiotensin II receptor could attenuate TLT formation and ensuing CKD after AKI. Method Ischemia-reperfusion injury (IRI) was used as AKI model. In vivo, systemic angiotensin II receptor blockade was performed by administration of an angiotensin II receptor antagonists called losartan after the recovery of AKI. Cell-specific angiotensin II receptor blockade was performed using Gli1-CreERT2;AT1Rfl/fl mice to knockout angiotensin II type 1a receptor in pericytes. We also investigated the effect of angiotensin II receptor blockade using 3T3 fibroblasts cell line. Results During the 8-month follow-up period after IRI, the activity of intra-renal renin–angiotensin system (RAS) elevated without treatment of losartan. We also displayed that multiple TLTs developed in ensuing CKD after IRI both in a CD-1 and C57BL/6J mice model, which were confirmed by staining of CD3 and B220 representing T and B lymphocytes, respectively. Notably, losartan could not only reduce the size and number of TLT, but also downregulate proinflammatory cytokines such as CXCL13, CCL21 and CCL19 which trigger the initiation of TLT. In vitro, using 3T3 fibroblasts cell line and primary pericytes isolated from kidney after IRI, angiotensin II administration could induce the development of fibroblasts with distinct phenotypes and stimulate production of aforementioned proinflammatory cytokines, particularly CCL19. Additionally, we discovered that angiotensin II-stimulated fibroblasts induced migration of lymphocytes via CCL19 production. Using Gli1-CreERT2;AT1Rfl/fl mice, we found that TLT formation decreased after IRI compared to control groups. Conclusion Losartan can reduce ensuing CKD and TLT formation. Distinctive pericytes inhibition by losartan is the plausible mechanism of amelioration of TLT formation. As a result, losartan might be the promising therapeutic agent to prevent AKI-CKD continuum.