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 6

Increased expression of Kim1 and dedifferentiation markers in uninjured PTEC DN RAR mouse kidneys.

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Increased expression of Kim1 and dedifferentiation markers in uninjured ...
(A) The percentage of the area of Kim1 staining, and the percentage of LTL+ PTECs that are Sox9+ or Ki67+ in the cortex and OSOM of uninjured PEPCK Cre+ and Cre– mice. Ki67, Sox9, and Kim1 staining in uninjured Cre+ and Cre– kidneys shown in Figure 5, B and D. (B) Renal Kim1, Sox9, and FoxM1 mRNA expression. (C) Tubular injury scores. (D) PAS-stained images showing areas with flattened epithelia (green arrow) and peritubular inflammatory cells (red arrow) in the OSOM of uninjured Cre+ and Cre– kidneys. Scale bars: 50 mM. The OSOM Sox9 and Ki67 data in A are the same as the uninjured controls in Figure 5, A and C. A–C used t tests, with P values comparing PEPCK Cre+ and Cre– mice.