Abstract: SA-PO118
Endothelial Nitric Oxide Synthase/Nitric Oxide Pathway Underlies the Mechanisms of AKI to CKD Transition via Prolonged Activation of the Wnt/β-Catenin Pathway
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kondo, Megumi, Kawasaki Medical School, Kurashiki, Japan
- Nagasu, Hajime, Kawasaki Medical School, Kurashiki, Japan
- Sogawa, Yuji, Kawasaki Medical School, Kurashiki, Japan
- Kadoya, Hiroyuki, Kawasaki Medical School, Kurashiki, Japan
- Kidokoro, Kengo, Kawasaki Medical School, Kurashiki, Japan
- Satoh, Minoru, Kawasaki Medical School, Kurashiki, Japan
- Kashihara, Naoki, Kawasaki Medical School, Kurashiki, Japan
Background
Acute kidney injury (AKI) is not always reversible, but often promotes to chronic kidney disease (CKD), known as “AKI to CKD transition.” Aging and disease conditions such as hypertension and diabetes are recognized as risk factors for AKI to CKD transition. These conditions are also closely associated with endothelial dysfunction (ED). Therefore, we hypothesized that AKI to CKD transition is promoted by ED characterized by deterioration in eNOS/Nitric Oxide (NO) /sGC/PKG pathway.
Methods
Wild-type mice (C57B6/J: WT) and eNOS deficient mice (eNOSKO) were used. WT and eNOSKO mice were divided into 4 groups: WT-sham, WT-IRI, eNOSKO-sham and eNOSKO-IRI. Mice were sacrificed on day 28 (D28) after ischemic reperfusion injury(IRI) (WT-IRI-D28 and eNOSKO-IRI-D28). To evaluate the therapeutic potential of sGC activation on the AKI to CKD transition, eNOSKO-IRI mice treated with PDE5 inhibitor (PDE5i, Sildenafil citrate , 5mg/kg/day, drinking water) from day 7 (D7) to day28 (D28) after IRI.
Results
Acute kidney damages of IRI were fully recovered in WT-IRI-D28 group. However, tubulointerstitial injuries, tubular cell damage, interstitial fibrosis and infiltration of inflammatory cells remained in eNOSKO-IRI-D28 group. These results indicate that deficient eNOS/NO/sGC/PKG signaling pathway promotes AKI to CKD transition after IRI. Next, the kidney damages in the early phase, day 1 and day 7, after IRI were examined in both groups. Histological examinations of kidney tissues failed to detect alterations in both groups at day 1 and day 7. However, RNA-seq analysis revealed significant increased expressions of Wnt/βcatenin-related genes and M2 macrophage (MΦ) related genes in eNOSKO-IRI-D7 group compared with WT-IRI-D7 group. In addition infiltration of M2 MΦ, evaluated by flow cytometric analysis, were increased in eNOSKO-IRI-D7 but not WT-IRI-D7. Furthermore, PDE5i treatment significantly ameliorated the kidney injuries compared with non-treated group.
Conclusion
Endothelial dysfunction, characterized by deterioration of eNOS/NO/sGC/PKG signaling pathway underlies prolonged activation of Wnt/βcatenin pathway and infiltration of M2 MΦ, thereby plays a pivotal role in AKI to CKD transition.