Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
JCI Insight. 2023 Oct 23;8(20):e173144. doi: 10.1172/jci.insight.173144.
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.
视黄酸受体 (RAR) 信号对于哺乳动物肾脏发育至关重要，但在成年肾脏中，其仅局限于偶尔的集合管上皮细胞。我们现在表明，在人脓毒症相关急性肾损伤 (AKI) 和 AKI 的小鼠模型中，近端肾小管上皮细胞 (PTEC) 中广泛重新激活了 RAR 信号。在 PTEC 中抑制 RAR 信号的遗传抑制可预防实验性 AKI，但出乎意料的是，与 PTEC 损伤标志物 Kim1 的表达增加相关。然而，抑制 PTEC RAR 信号的保护作用与 Kim1 依赖性凋亡细胞清除（或噬作用）的增加有关，这与 PTEC 的去分化、增殖和代谢重编程有关。这些数据表明，重新激活 RAR 信号在调节人及实验性 AKI 中 PTEC 分化和功能中发挥了功能作用。
