Ischemia/reperfusion (IR)-induced acute kidney injury (AKI) occurs in a range of clinical settings and is characterized by pronounced inflammation, but the underlying regulatory mechanisms remain incompletely understood. Tiki2 is a Wnt inhibitor that is highly expressed in the kidney and its function has not been defined. Here, we show that Tiki2 is enriched in proximal tubular epithelial cells (PTECs) and is dynamically regulated during IR-induced AKI. Tubule-specific ablation of Tiki2 exacerbates immune cell infiltration and tubular injury following IR. Mechanistically, loss of Tiki2 leads to increased activation of Wnt5a/Ror signaling, which is induced in PTECs after IR injury, resulting in increased JNK and ERK activation and elevated expression of chemokines and cytokines that promote the infiltration of immune cells. Notably, the aggravated injury and inflammation caused by Tiki2 deficiency are reversed by Ror2 knockdown in PTECs. Together, these findings identify Tiki2 as a negative regulator of Wnt5a/Ror signaling in renal tubular cells and highlight the Tiki2-Wnt5a/Ror axis as a potential therapeutic target in IR-induced AKI. Tiki2 restrains Wnt5a/Ror signaling to limit inflammatory responses and immune cell infiltration in ischemia/reperfusion-induced acute kidney injury.
Yang et al. (Tue,) studied this question.