Renal fibrosis, characterized by excessive accumulation of the extracellular matrix in the renal tubulointerstitium, can lead to chronic kidney disease (CKD), resulting in a heavy burden on families and society. Clinical studies have shown that smoking is closely associated with CKD deterioration in patients with diabetes, hypertension, polycystic kidney disease, and kidney transplantation. However, the mechanism of action of nicotine in renal fibrosis pathogenesis remains largely unknown. X-linked inhibitor of apoptosis (XIAP), a member of the inhibitor of apoptosis protein (IAP) family, is involved in apoptosis, necroptosis, autophagy, and immune response. Here, the upregulated expression of XIAP and α7 nicotine acetylcholine receptor (α7-nAChR) was determined in the kidneys of the CKD smoking group in human and animal studies. A significant positive correlation between XIAP and cotinine was observed. In addition, the nuclear translocation and transcriptional activity of SP1 were promoted when nicotine bound to α7-nAChR, resulting in XIAP overexpression and renal interstitial fibrosis progression. This phenotype can be reversed by the nicotine receptor subtype α7-nAChR antagonists methyllycaconitine. Our results revealed the complex underlying mechanism of nicotine in promoting renal fibrosis by altering SP1 nucleocytoplasmic translocation and regulating XIAP expression. These results provide novel insights into the pathogenesis and treatment of CKD.
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