Abstract: FR-PO388
Grem1 Plays a Vital Role in Nicotine Exacerbated Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Wen, Hongxiu, Southwest Medical University, Luzhou, Sichuan, China
- Lan, Xiqian, Southwest Medical University, Luzhou, Sichuan, China
- Kumar, Vinod, Fienstine Institute for Medical Research, NEW YORK, New York, United States
- Marashi Shoshtari, Seyedeh Shadafarin, The Feinstein Institute for Medical Research, Manhasset, New York, United States
- Aslam, Rukhsana, Feinstein Institute for medical research, Glenoaks, New York, United States
- Hussain, Ali, Feinstein Institute of Medical Research, New York, New York, United States
- Malhotra, Ashwani, Feinstein Institute Medical Research and NSLIJ, MANHASSET, New York, United States
- Singhal, Pravin C., North Shore LIJ Health System, Great Neck, New York, United States
Background
Increasing evidences have demonstrated that cigarette smoking promotes the progression of diabetic nephropathy (DN), but the underlying molecular mechanisms are far from clear. Nicotine, a major component for smoking addiction, has been reported to be an independent component to cause kidney cell injury to accelerate the progression of DN. This study has been designed to evaluate the role of nicotine in DN and to explore the underlying molecular mechanisms.
Methods
In vivo studies, diabetic mice were developed through the administration of three doses of streptozotocin (STZ, 50 mg/kg body weight, intraperitonelly). These mice were fed with either nicotine (100 μg/ml) or vehicle (PBS) in their drinking water for 5 months. At the end of the experimental period, kidney function biomarkers (proteinuria, blood urea nitrogen [BUN]) were collected and kidneys were harvested for histological changes and molecular analysis (immunohistochemistry, real-time PCR, and Western blotting). The kidney transcriptomes of these mice were compared through RNA seq analysis, and the results were further confirmed by real-time PCR, Western blotting, and immunohistochemical studies. In vitro studies, human podocytes were treated with high glucose (30 mM) with or without nicotine (10 μM), followed by morphologic assay for apoptosis. The effect of high glucose with or without nicotine was also evaluated on podocytes-silenced for specific genes.
Results
In vivo studies, STZ-receiving mice displayed a higher level of blood glucose and associated kidney injury, however, nicotine further exacerbated this effect of hyperglycemia. Interestingly, nicotine alone didn't cause an over kidney injury. RNA seq analysis revealed that nicotine dramatically exacerbated the expression of Grem1, a DAN family member, which has been demonstrated to play a vital role in the pathogenesis of DN. In vitro studies, combined use of nicotine and high glucose displayed an increase in podocyte apoptosis as well as the expression of Grem1; while silencing of Grem1 decreased the number of cells with apoptosis.
Conclusion
Grem1 might play an important role in nicotine-exacerbated DN. Our study has highlighted novel molecular targets for the therapy and prevention of smoking boosted DN.