Abstract: FR-OR07
Compartment-Specific Role of Retinoic Acid Receptor Activation in AKI
Session Information
- AKI: Novel Mechanisms and Targets of Injury
November 05, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Min, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Lopez, Lauren N., University of California Davis, Davis, California, United States
- Delgado, Rachel, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Brewer, Maya, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Gewin, Leslie S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Retinoic acid receptors (RARs) are activated in proximal tubules (PT), collecting duct (CD), and renal macrophages (Møs) after ischemia reperfusion AKI (IR-AKI), and systemic RAR inactivation increases Mø-dependent injury after IR-AKI. However, the functional roles of RAR activation in different cellular compartments are unknown.
Methods
RARE-LacZ (RAR reporter); PEPCK-CRE; R26R-Dominant Negative RAR (PT-DNRAR); AQP2-CRE; DNRAR (CD-DNRAR); LysM-CRE; DN-RAR (Mø-DNRAR) underwent bilateral IR- and/or rhabdomyolysis-AKI (rhabdo-AKI). Injury and RARE-LacZ localization were evaluated by BUN, LacZ staining and IF. Renal Mø activation determined by FACS; primary PTEC proliferation and metabolic activity using Seahorse.
Results
RARs are more widely activated after rhabdo- vs. IR-AKI: ~90% in LTL or Kim1+ PTECs; ~5% in AQP2+ CD; ~2-3% in F4/80+ Møs; and <2% in THP1+ thick ascending limb. To evaluate RAR function, we performed IR- and rhabdo-AKI in PT-, CD- and Mø-DNRAR mice. AKI was less severe in PT-DNRAR mice: day 3 BUN in CRE- vs. +; rhabdo-AKI: 52.9 (11.2) vs. 29.1 (1.8); IR-AKI: 71.7 (8.8) vs. 38.4 (8.3) mg/dl, p<0.005. In contrast, Mø-DNRAR had more severe injury: IR-AKI, day 3 BUN CRE- vs. + 37.0 (2.9) vs. 63.1 (10.6), p<0.05. There was no difference in IR- or rhabdo-AKI severity in CD-DNRAR mice. Despite decreased injury, there was increased Kim1 and F4/80+ Møs after AKI, associated with decreased MLKL (necrosis) and increased Sox9 and Ki67 (de-differentiation and repair) in PT-DNRAR mice. FACS also showed decreased Ly6C inflammatory renal Møs after AKI. Uninjured PT-DN-RAR mice also had patchy increase in Kim1/Sox9+ PTECs; increased F4/80+ CD206+ reparative Møs; and PTECs from PT-DNRAR CRE+ mice were more metabolically active and proliferative than CRE- mice.
Conclusion
Inhibition of RAR in PTs protects against AKI by increasing reparative, metabolically active PTECs, and suppresses Mø activation, while inhibition of RAR in Møs exacerbates AKI. In contrast, inhibition of RARs in CDs does not affect the severity of injury. These findings indicate that RAR activation in different cellular compartments exert opposing effects on the severity AKI through distinct mechanisms, and provides the first evidence that dedifferentiated and inflammatory PTECs, recently described molecular signatures of failed repair, may be protective in AKI.
Funding
- NIDDK Support