Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression

Molecular Medicine

Research Article

Rui Xue¹  Jianning Chen¹  Syed Faizan Mehdi²  Pravin Singhal²  Ashwani Malhotra²  Vinod Kumar²  Rukhsana Aslam²  Haiting Xiao³  Xiqian Lan³  Huairong Luo³ 

[1] Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, 310000, Hangzhou, Zhejiang, China;Feinstein Institute for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 11030, Manhasset, NY, USA;Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, 646000, Luzhou, Sichuan, China;

关键词: Grem1;    Nicotine;    Diabetic nephropathy;    TGF-β;    Therapeutic target;   

DOI  :  10.1186/s10020-023-00692-9

 received in 2022-08-29, accepted in 2023-06-27,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundDiabetic 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.MethodIn 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.ResultNicotine 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.ConclusionGrem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

40648_2023_255_Article_IEq12.gif

Fig. 10

12936_2023_4510_Article_IEq8.gif

Fig. 4

41239_2023_389_Article_IEq72.gif

Fig. 1

Fig. 2

Fig. 2

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 2