ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-OR07

Compartment-Specific Role of Retinoic Acid Receptor Activation in AKI

Session Information

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