Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury
Min Yang, Lauren N. Lopez, Maya Brewer, Rachel Delgado, Anna Menshikh, Kelly Clouthier, Yuantee Zhu, Thitinee Vanichapol, Haichun Yang, Raymond C. Harris, Leslie Gewin, Craig R. Brooks, Alan J. Davidson, Mark de Caestecker
Min Yang, Lauren N. Lopez, Maya Brewer, Rachel Delgado, Anna Menshikh, Kelly Clouthier, Yuantee Zhu, Thitinee Vanichapol, Haichun Yang, Raymond C. Harris, Leslie Gewin, Craig R. Brooks, Alan J. Davidson, Mark de Caestecker
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Research Article Nephrology

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Abstract

Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was associated with dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.

Authors

Min Yang, Lauren N. Lopez, Maya Brewer, Rachel Delgado, Anna Menshikh, Kelly Clouthier, Yuantee Zhu, Thitinee Vanichapol, Haichun Yang, Raymond C. Harris, Leslie Gewin, Craig R. Brooks, Alan J. Davidson, Mark de Caestecker

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Figure 7

Inhibition of RAR signaling increases proliferation, glycolysis, and oxidative phosphorylation in cultured PTECs.

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Inhibition of RAR signaling increases proliferation, glycolysis, and oxi...
Data are shown for replicates performed on separate preparations of primary PTECs isolated from different mice. (A) RAR target genes. (B) Expression of Kim1 mRNA. (C) Cell growth. Cell numbers/10× microscopy field at the indicated time points in PTECs from 4 PEPCK Cre+ and 4 Cre– mice. (D) Glycolytic stress tests on PTECs from 6 Cre+ (red) and 6 Cre– (black) mice. (E) Glycolytic rate, maximal glycolytic capacity, and glycolytic reserve. (F) Mitochondrial stress test. (G) Basal mitochondrial respiration, maximal mitochondrial respiration, and spare respiratory capacity. A, E, and G used t tests, with P values comparing PEPCK Cre+ and Cre– PTECs. D and F used 2-way ANOVA, with P values comparing PEPCK Cre+ and Cre– PTECs over time.