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Abstract: FR-PO593

PBI-4547 Prevents Renal Destruction and Fibrosis in Severely Obese db/db Mouse Model of Diabetes-Induced Kidney Disease

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Leblond, Francois A., Prometic BioSciences Inc., Laval, Quebec, Canada
  • Létourneau, Sylvie, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Ouboudinar, Jugurtha, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Gervais, Liette, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Laurin, Pierre, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Grouix, Brigitte, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Gagnon, Lyne, Prometic BioSciences Inc., Laval, Quebec, Canada
Background

Type 2 diabetes (T2D) is a major health problem worldwide. Comorbidities, such as kidney disease, associated to T2D are numerous and cause severe reduction of life expectancy. The uninephrectomized (NX) diabetic (db/db) mouse is a widely used model for the study of comorbidities associated to T2D. It also allows to study effects of obesity on diabetes-induced kidney disease. PBI-4547 is an orally active compound that displays anti-fibrotic and metabolic activities via a novel mechanism of action. The aim of this study was to investigate the protective effect of PBI-4547 on kidney health and function in NX db/db mice.

Methods

Total nephrectomy of the right kidney was performed on day 0 on 6-weeks old db/db (B6.BKS(D) and control C57BL/6 mice. Animals were treated with vehicle or PBI-4547 (25 mg/kg) from day 1 through 105 by daily oral gavage.

Results

PBI-4547 significantly improved diabetic condition of db/db mice, and lowered weight gain to that of control C57BL/6 mice. A significant reduction of fasting blood glucose, plasma insulin, and area under the curve in oral glucose tolerance test were observed in PBI-4547-treated db/db mice. PBI-4547 dosing also resulted in a reduction of plasma triglycerides and an increase in adiponectin. Moreover, PBI-4547 eventuated a significant reduction in the renal damage observed on db/db mice as shown by histopathological analysis of kidneys. When compared to control C57BL/6 mice, kidney glomeruli, tubules and capillaries of non-treated db/db mice were found significantly damaged. These modifications were almost absent on db/db mice treated with PBI-4547. Evaluation of numerous markers of fibrosis also confirmed that PBI-4547 significantly reduced the fibrosis process in the kidney. Reduction of the mRNA expression of collagen type 1 (-40%), MCP-1 (-63%), TIMP-1 (-71%), MMP-2 (-47%) and GLEPP-1 (-13%) were shown in kidneys of PBI-4547-treated compared to untreated db/db mice. Neither BUN nor GFR were found significantly modified in the db/db non-treated mice (compared to NX C57BL/6 mice) and PBI-4547 had no impact on these parameters.

Conclusion

These studies suggest that, in addition to the improvement of T2D, PBI-4547 treatment precludes renal structure destruction and prevents fibrosis in the kidneys of severely obese db/db mice.

Funding

  • Commercial Support