Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression

Abstract

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 hyperglycemia or nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and worsened DN. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury. Conclusion Grem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN.

The Molecular Mechanism of Renal Tubulointerstitial Inflammation Promoting Diabetic Nephropathy

“… 41 Moreover, our recent study showed that the oxidative stress response in DN was significantly enhanced and that the TGF-β signaling pathway was activated considerably, with significantly increased levels of Smad2/3 and Smad1/5/8 proteins phosphorylation. 42 This may enhance renal fibrosis and further compromise renal function in the diabetic milieu.…”