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Background Diabetic nephropathy (DN) is a major complication of diabetes mellitus. The tobacco epidemic exacerbates kidney damage in patients with DN. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, including 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, Nicotine + diabetic) by intraperitoneal injection of Nicotine or PBS. After another 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 in vitro studies, we used siRNA to suppress Grem1 expression in human podocytes and then 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, and the expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, and western blot analysis revealed that, compared to hyperglycemia or Nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and activated the TGF-β pathway. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury. Conclusion Grem1 plays a vital role in the nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN. |
