PS-B09-2: ENOS-NO PATHWAY MODULATES AKI TO CKD TRANSITION IN IRI MODEL MICE VIA REGULATION OF B;CATENIN TRANSLOCATION

Abstract

Background: The incidence of acute kidney injury (AKI) has increased over the past few decades. AKI is also currently recognized as an inducer of chronic kidney disease (CKD) through a process known as the AKI to CKD transition. It has been shown that aging and hypertension are risk factor for the AKI to CKD transition. Because these conditions are related to endothelial dysfunction, we hypothesized that the AKI to CKD transition is promoted by deficiency in the eNOS Nitric Oxide (NO) pathway as an endothelial dysfunction, and we used eNOS deficient mice (eNOSKO) and wild-type (WT) mice (C57B6/J: WT) to determine the mechanism of the AKI to CKD transition. Methods: WT and eNOSKO mice were used to determine the role of the eNOS NO pathway. Ischemic reperfusion was performed two weeks after uni-nephrectomization. The ischemic time was 20 min. The WT and eNOSKO mice were divided into four groups: WT sham, WT ischemic reperfusion injury (IRI), eNOSKO-sham and eNOSKO IRI. The first theses mice were sacrificed on Day 28 (D28) after the IRI (WT IRI D28 and eNOS IRI D28). Pathological analysis was conducted using Masson staining and KIM1 staining. Inflammation was assessed using quantitative PCR (qPCR) (IL1β;, IL6, and F4/80) and flow cytometry (FACS) analysis. Results: There was no evidence of kidney damage in the WT IRI D28 group. However, KIM1 staining detected tubular cell damage in the eNOSKO IRI D28 group. Fibrosis, which was assessed using the Masson staining, was also exacerbated in the eNOSKO IRI D28 group compared with the WT IRI D28 group. These results suggested that deficient eNOS NO signaling promoted the AKI to CKD transition. Next, the WT-IRI and eNOS IRI mice were sacrificed on Day 1 (D1) after the IRI (WT IRI D1 and eNOSKO IRI D1) to evaluate inflammation and kidney damage in the acute phase after IRI. There were no differences in kidney damage and inflammation between the WT-IRI-D1 and eNOSKO-IRI-D1 groups. In addition, at each time point (D7, Day 14 (D14), and D28) after IRI, qPCR was used to detect Wnt β;catenin related gene expression in the entire kidney. Expression of these genes was increased in the eNOSKO IRI D7 group compared with the WT IRI D7 group. Conclusions: Our results showed that after ischemic reperfusion, deficiency in the eNOS NO pathway promotes the AKI to CKD transition via acceleration of Wnt β;catenin. Therefore, activation of the eNOS NO pathway could be a potential therapeutic target in AKI.