Wnt5a Promotes AKI to CKD Transition via p-JNK/Snai1 Signaling

Background: The transition from acute kidney injury(AKI) to chronic kidney disease(CKD) is the major obstacle in the clinical treatment of AKI. In our previous study, we found Wnt5a-induced noncanonical signaling is a contributing mechanism for renal tubular inflammation in diabetic nephropathy. However, its role of Wnt5a in AKI to CKD transition still remains unknown. Methods: Renal biopsy sample of 10 AKI patients and their clinical data were collected to analyze the correlation of Wnt5a with renal function and pathological characteristics. Wnt5a knockdown mice (Wnt5a+/-) was generated, and two animal models of AKI by inducing renal ischemia-reperfusion (IRI) or unilateral ureteral obstruction (UUO) were established with the observation of 2 weeks post-surgery. In vitro, HK-2 cells were treated with transforming growth factor-β (TGF-β) or oxygen-glucose deprivation (OGD). RNA-sequencing was introduced to detect the downstream mechanism of Wnt5a signaling. Results: The expression of Wnt5a in the kidney section of AKI patients was significantly increased mainly in the renal proximal tubules, and was associated with the decline in kidney function and interstitial fibrosis. In mice with IRI or UUO, Wnt5a elevation promoted the phosphorylation of JNK (p-JNK), increased the expression of Snai1, a transcription factor well known for inducing renal fibrogenesis. In a global Wnt5a knockdown (Wnt5a+/-) mouse model subjected to IRI or UUO, reduction of Wnt5a alleviated renal tubule injury and interstitial fibrosis, attenuated the progression from AKI to CKD. in vitro, inhibition of Wnt5a in OGD induced HK-2 cells suppressed expression of p-JNK and Snai1, suggesting a strong association between Wnt5a/p-JNK and Snai1. Conversely, overexpression of Wnt5a in HK-2 cells increased the expression of p-JNK and Snai1, thus aggravated renal fibrosis. We further found a direct binding between p-JNK and Snai1 by Co-IP and mutation of JNK phosphorylation site (T183A) reduced the expression of Snai1, indicating a p-JNK/Snai1 pathway downstream of Wnt5a. Conclusion: Our data revealed that Wnt5a is a key molecule mediating the progression from AKI to CKD, which shed light on the new Wnt5a/p-JNK/Snai1 pathway in AKI to CKD transition.