HIF-PHI regulates the STING-TBK1-IRF3 signaling pathway and mediates macrophage polarization to alleviate renal interstitial fibrosis

Abstract Purpose: Hypoxia-inducible factor proline hydroxylase inhibitors (HIF-PHIs) may affect the STING-TBK1-IRF3 pathway by targeting the polarization of macrophages to prevent the progression of Renal interstitial fibrosis (RIF). However, the mechanism of action remains unclear. Methods: A total of 60 patients were enrolled in the clinical study with 30 each for control and RIF group. Kidney tissue and blood samples were collected and the expression of M1-type macrophage markers (MHC-II, CD86) and components of the STING pathway (STING, P-IRF3, IRF3), together with MCP-1/CCL2 and TNF-α were examined. THP-1 and HK-2 cells were treated with a STING pathway activator (SR-717) and inhibitor (H151). A mouse model of kidney fibrosis was also established to examine the effects of HIF-PHI. Results: The expression levels of MCP-1/CCL2, TNF-α, iNOS, CD86 and STING protein were significantly higher in RIF patients than controls. Treatment of THP-1 cells with SR-717 led to a significant increase in CD86, MHC-II, TNF-α , IL-6 and IFN-γ expression levels (P<0.05), while H151 had no effect (P>0.05). The expression of ECM deposition markers including α-SMA, fibronectin, and collagen IV was higher in TGF-β-induced HK-2 cells, but reduced following H151 treatment (P<0.05). HIF-PHI treatment of RIF mice led to a significant reduction in serum creatinine and blood urine nitrogen, CD86 and MHC-II, STING, α-SMA, collagen IV, and fibronectin expression levels (P<0.05). Conclusions: HIF-PHIs reduced the infiltration of M1-type macrophages and release of inflammatory factors in the kidneys of mice through inhibition of the STING-TBK1-IRF3 pathway, thereby reducing kidney damage and ECM deposition.