Characterization of Inflammation, Fibrosis, Zinc dyshomeostasis, Gut microbiota, Metabolomics in Cadmium-induced Diabetic Nephropathy, accompanied by the Protective Effects of Zn(II)-curcumin
Cadmium (Cd) is known as a common environmental pollutant that contributes to the incidence of diabetes and insulin resistance. However, the underlying mechanism remains unclear. Dietary zinc is required to maintain steady-state tissue zinc levels and intestinal homeostasis and may yield therapeutic benefits in diseases associated with zinc dysregulation or gut dysbiosis. Here, we investigated the effects of Cd and dietary Zn(II)-curcumin solid dispersions (ZnCM) in diabetic nephropathy (DN) rats. Rats were orally administered Cd daily over four weeks, injected with Streptozotocin and orally administered ZnCM daily over eight weeks. The results indicated that Cd promoted renal dysfunction, inflammation, fibrosis and related TLR4/NF-?B and TGF-ß1/Smad signaling pathways, microbial and metabolism disorders in DN rats. Importantly, ZnCM mitigated these effects. Besides, we found Clostridium_sensu_stricto_1, Klebsiella and Phascolarctobacterium might regulate the levels of Lumichrome and Lysine production, and these further suppressed the secretion of TNF-a, IL-1ß and IL-6, regulating pro-inflammatory responses or immune disorders. Notably, the regulation of renal function and inflammation effects of Cd and ZnCM were verified through fecal microbial transplantation. This preliminary study provides new insight into the potential mechanisms of Cd-induced DN, and ZnCM has potential as a simple, safe, effective therapy to alleviate Cd-induced DN.