Abstract: FR-PO390
Activation of Pro-Fibrotic Genes by Nicotine in a Mouse Model of Diabetes: Implications for Diabetic Nephropathy in Smokers
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
- Feng, Wenguang, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Jaimes, Edgar A., Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Background
Tobacco use is a well-recognized, preventable risk factor for CKD progression, especially in diabetics; however, the mechanisms involved are not completely understood. We and others have demonstrated that nicotine acetylcholine receptors (nAChR) are present in rat, mouse, and human kidneys, and that the systemic administration of nicotine worsens the severity of renal injury in animal models of CKD. In these studies we hypothesize that siganling via the α7-nAChR promotes the gene expression of pro-fibrotic pathways in diabetic mice receiving nicotine.
Methods
Diabetes (DM) was induced by low dose STZ injection in male eNOS-/- mice (n=6 per group). After confirmation of diabetes nicotine was admnistered in the drinking water (Nic, 100 μg/mL) for 10 weeks. A group of mice was treated with the specific α7nAChR blocker IC200610 (NB, 2 mg/kg IP) 5 days a week for 10 weeks. An additonal group of mice double knockout for eNOS and α7nAChR was also made diabetic (DKDM) and treated with nicotine (Nic, 100 μg/mL). After euthanasia renal cortex mRNA expression for genes involved in fibrosis and inflammation was determined by RT-PCR.
Results
Diabetes resulted in increased expression of genes linked to fibrosis and inflammation (table). The administration of nicotine increased the expression of CTGF, COL1 and MMP2 three genes that have been linked to progression of CKD. The administration of a specific α7nAChR blocker or genetic deletion of α7nAChR reduced the expression of these genes suggesting that these effects are mediated via signaling activated by this receptor.
Conclusion
The administration of nicotine to diabetic mice results in increased expression of CTGF and MMP2 two genes involved in the pathogenesis of progressive CKD including diabetic nephropathy. In addition these effects appear to be mediated by the α7nAChR which could potentailly be a therapeutic target for diabetes with CKD who use nicotine containing tobacco products.
Gene expression in diabetic mice on nicotine
| FN | CTGF | CCL2 | MMP2 | MMP9 | COL1 | COL4 | TGFβ | |
| Control | 1.0±0.3 | 1.1±0.4 | 1.1±0.3 | 1.0±0.2 | 1.0±0.5 | 1.0±0.1 | 1.0±0.2 | 1.1±0.3 |
| DM | 4.5±0.8* | 1.9±0.1* | 6.7±0.3* | 2.8±0.3* | 2.6±1.0* | 2.2±0.4* | 2.1±0.2* | 2.0±0.2* |
| DM+Nic | 4.3±0.7* | 2.6±0.2*,# | 6.0±1.1* | 3.6±0.6*,# | 1.6±0.2 | 3.5±0.6*,# | 2.6±0.1* | 2.1±0.1* |
| DM+Nic/NB | 2.3±0.5** | 1.0±0.1** | 4.7±1.1** | 2.7±0.3 | 1.0±0.1** | 2.7±0.3 | 2.0±0.6 | 1.3±0.2** |
| DKDM+Nic | 1.5±0.2** | 0.7±0.1** | 1.6±0.3** | 1.8±0.3** | 0.5±0.1** | 1.0±0.4** | 0.7±0.1** | 0.7±0.1** |
* P <0.05 vs Control, ** P <0.05 vs DM and DM+Nic, # P<0.05 DM (N=6 per group)
Funding
- Other NIH Support