Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression

作者：Jianning Chen, Haiting Xiao, Rui Xue, Vinod Kumar, Rukhsana Aslam, Syed Faizan Mehdi, Huai‐Rong Luo, Ashwani Malhotra, Xiqian Lan, Pravin C. Singhal · 发表于：Molecular Medicine · 年份：2023 · DOI：10.1186/s10020-023-00692-9 · 被引用次数：11 · 研究领域：Renin-Angiotensin System Studies、Galectins and Cancer Biology、Chronic Kidney Disease and Diabetes

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, and the tobacco epidemic exacerbates kidney damage in patients with DN. However, the underlying molecular mechanisms remain unclear. METHOD: In the present study, we used a diabetic mouse model to investigate the molecular mechanisms for nicotine-exacerbated DN. Twelve-week-old female mice were injected with streptozotocin (STZ) to establish a hyperglycemic diabetic model. After four months, the control and hyperglycemic diabetic mice were further divided into four groups (control, nicotine, diabetic mellitus, nicotine + diabetic mellitus) by intraperitoneal injection of nicotine or PBS. After two months, urine and blood were collected for kidney injury assay, and renal tissues were harvested for further molecular assays using RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry. In vitro studies, we used siRNA to suppress Grem1 expression in human podocytes. Then we treated them with nicotine and high glucose to compare podocyte injury. RESULT: Nicotine administration alone did not cause apparent kidney injury, but it significantly increased hyperglycemia-induced albuminuria, BUN, plasma creatinine, and the kidney tissue mRNA expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry analysis revealed that, compared to hyper...