Shengqing Jiangzhuo Capsule Alleviates Intestinal Inflammation in Chronic Kidney Disease by Downregulating CHAC1 to Inactivate the HIF-1 Pathway.

BACKGROUND: Chronic kidney disease (CKD) imposes significant global health burdens. Shengqing Jiangzhuo (SQJZ) capsule possesses potential to alleviate CKD via gut-kidney axis, with the specific role and mechanisms involving CHAC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) and hypoxia-inducible factor 1 (HIF-1) signaling remaining unclear. METHODS: Adenine-induced CKD rats were treated with SQJZ capsule for 4 weeks. The levels of blood urea nitrogen (BUN), serum creatinine (SCR), urine albumin/creatinine ratio (ACR), and inflammatory markers in colon tissues, including proinflammatory cytokines and oxidative markers, were assessed via enzyme-linked immunosorbent assay (ELISA). The renal pathology was estimated by histopathology. Transcriptomic sequencing combined with bioinformatics analysis identified the downstream pathway regulated by SQJZ in colon tissues. In vitro, after treatment with CHAC1 knockdown or HIF-1α activation, lipopolysaccharide (LPS)-treated NCM460 cells were analyzed for apoptosis, detected by flow cytometry, and inflammatory marker levels, determined by ELISA. RESULTS: SQJZ significantly reduced serum BUN, SCR, and urinary ACR in CKD rats, ameliorating histopathological damage. In colon tissues, SQJZ suppressed proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), and oxidative markers, reactive oxygen species (ROS), and malondialdehyde (MDA), while elevating superoxide dismutase activity. Transcriptomics revealed SQJZ-mediated regulation of HIF-1. CHAC1 knockdown in vitro reduced LPS-induced apoptosis and inflammation, while HIF-1α activation reversed these effects. Additive suppression of inflammation was observed in NCM460 cells with combined CHAC1 knockdown and SQJZ treatment. CONCLUSION: SQJZ alleviates intestinal inflammation in CKD, potentially mediated by downregulation of CHAC1 and subsequent inactivation of the HIF-1 pathway, positioning SQJZ as a promising gut-targeted therapy in CKD.