Abstract: FR-PO1083
Establishment and Application a Novel Reversible Unilateral Ureteral Obstruction (RUUO) Mouse Model and in Mechanism Study of AKI to CKD
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Mao, Xinyue, Hainan Medical University, Haikou, Hainan , China
- Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Li, Bing, Hainan Medical University, Haikou, Hainan , China
Background
Acute kidney injury (AKI) is a worldwide health problem. About 35-71% of AKI progress to chronic kidney disease (CKD) due to renal repair failure. Studies on the progression of AKI to CKD are focused on animal models of prerenal and renal AKI. It is necessary to establish an animal model to investigate the progression of postrenal AKI to CKD.
Methods
We established a RUUO mouse model. In brief, we ligated the left ureter to create a ureteric obstruction in mice. After 5 or 10 days, ureteral obstruction was removed by the coindication of the ureter and bladder. Three days later, we performed the right nephrectomy and then monitor renal function and molecular mechanisms on the left kidney with IF and IHC staining, scanning electron microscopy and flow cytometry analysis.
Results
We observed adaptive and maladaptive repairs in 5 and 10 days RUUO kidneys. During the complete recovery of AKI in 5 days RUUO kidneys, 1) the infiltration of M2 macrophages marked by F4/80 + CD206 and CD11b + ly6Cint was increased; 2) the expression of inflammatory factors (TNF-α, IL-1β, IL-6 and IL-4, IL-10), autophagy components (Beclin-1, Bcl-2, BNIP3, LAMP2, LC3BII/I and P62), and HIF-1α and HIF-2α, and the population of peritubular capillaries (PTC) (VEGF and CD31) were normalized to baseline; and 3) the activation of pericytes into myofibroblasts was blocked and alleviated as examined by PDGFRβ+α-SMA staining. In the process of AKI to CKD in 10 days RUUO kidneys, 1) M1 macrophages marked by F4/80+iNOS and CD11b+Ly6Chigh were dominant at the beginning, and then gradually transformed into pro-fibrotic CD11b+Ly6Clow cells; 2) the expression of pro-inflammatory factors was high, but the expression of antiinflammatory factors was low; 3) the expression of the components of autophagy was decreased and would not be recovered; 4) the population of PTC maintained at low level; 5) pericytes were constantly be activated into myofibroblasts to form fibrosis, and 6) the expression of HIF-1α and HIF-2α was initially increased, then decreased to baseline (normal) level but increased again in the late stage.
Conclusion
With our new RUUO mouse model, we confirm that renal adaptive repair occurs in 5-days-RUUO kidneys to simulate the complete recovery of AKI, whereas renal maladaptive repair occurs in 10-days-RUUO kidneys to simulate the progression from AKI to CKD.