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Abstract: TH-PO101

Inhibition of Retinoic Acid Signaling in Proximal Tubules Protects Against AKI by Enhancing Kim1-Dependent Efferocytosis

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Yang, Min, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Gewin, Leslie S., Washington University in St Louis, St Louis, Missouri, United States
  • Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Retinoic acid receptor (RAR) signaling is activated in proximal tubules (PTs) and macrophages (Møs) after IRI-AKI, and systemic inhibition of RARs increases Mø-dependent injury after IRI-AKI. It is unknown whether RARs are activated in other forms of AKI, and the functional role of PT RAR signaling after AKI remains unknown.


GSEA for RAR targets enriched in a snRNA seq database from patients with sepsis-associated AKI (SA-AKI) (Hinze, 2022). RARE-LacZ (RAR reporter mice); PEPCK-CRE; R26R-dominant negative RAR (PT-DN RAR), bilateral IRI- or rhabdomyolysis-AKI (rhabdo-AKI). Injury and RARE-LacZ localization evaluated by BUN, QRT-PCR, LacZ staining, and IF. Renal Møs by RNA seq and FACS; PT proliferation, metabolic activity, and Kim-1 function in primary PTs. Efferocytosis by quantifying PT apoptosis +/- a lysosome inhibitor, Bafilomycin, after IRI-AKI.


These is enrichment for RAR targets in PTs from patients with SA-AKI. The same gene set was upregulated in mouse kidneys after rhabdo-AKI. In contrast to IRI-AKI where reporter activation was transient, there was prolonged activation of RARE-LacZ in PTs throughout the kidney after rhabdo-AKI. Inhibition of PT RAR signaling in PT-DN RAR mice protected against acute tubular injury (ATI) in rhabdo-, and to a lesser extent, IRI-AKI. This was unexpectedly associated with increased Kim-1 expression; PT de-differentiation, proliferation, and metabolic reprogramming (increased glycolysis and ox phos), in PT-DN RAR kidneys and cultured PTs. Kim-1-dependent uptake of oxidized LDL was increased in PT-DN RAR PTs, and there was reduced PT apoptosis after IRI- and rhabdo-AKI. This was reversed by Bafilomycin treatment, indicating that decreased apoptosis is dependent on PT efferocytosis. Consistent with increased efferocytosis as a protective mechanism in AKI, there was also a reduction in pro-inflammatory renal Møs after IRI-AKI in PT DN RAR mice.


These findings indicate that there is extensive activation of PT RAR signaling in experimental and human AKI, and that inhibition of RAR signaling in PTs protects from AKI by promoting PT de-differentiation and enhancing Kim-1 dependent efferocytosis. This suggests that activation of RAR signaling in PTs after AKI is a compensatory response that reestablishes PT differentiation and function after ATI.


  • NIDDK Support