EXPLORING THE GUT-KIDNEY-AXIS IN A MOUSE MODEL OF DIABETIC KIDNEY DISEASE
Miss Amalia S. Khayyira1, Dr. Sih Min Tan1, Dr. Matthew Snelson2, Miss Inez A. Trambas1, Mrs. Adrienne Laskowski1, Dr. Arpeeta Sharma1, Dr. Melinda T. Coughlan1
1Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, Australia, 2Hypertension Research Laboratory, School of Biological Science, Monash University, Clayton, Australia
Aim: To investigate whether larazotide can improve diabetic kidney disease (DKD) in a mouse model of type 2 diabetes.
Background: Emerging research has unveiled a potential link between intestinal barrier integrity and kidney injury, known as the gut-kidney-axis. We have shown evidence of an impaired intestinal epithelial barrier in a mouse model of DKD (LepR db/db mice). Larazotide is purposed to target the gut to improve intestinal permeability, but it has not been investigated in DKD.
Methods: Eight-week-old LepR db/db mice were treated with 20mg/kg/day larazotide in drinking water for 10 weeks. FITC-dextran was used in vivo to assess intestinal tight junction permeability. Kidney injury was evaluated by urinary albumin-creatinine ratio, and structural damage was assessed by periodic acid Schiff staining and glomerulosclerotic index scoring.
Results: Diabetic LepR db/db mice displayed greater intestinal permeability when compared to non-diabetic controls, as shown by the FITC-dextran assay (4.322±1.081µg/ml vs 1.597±1.126µg/ml, p<0.05) which was not improved by larazotide treatment. Unexpectedly, larazotide exacerbated albuminuria in diabetic mice (81.81±28.38µg/µmol vs 125.6±34.93µg/µmol, p<0.05). This finding corresponds to the further increase in kidney weight in the larazotide-treated diabetic mice (0.014±0.002 vs 0.013±0.001, p<0.05). No changes in glomerulosclerosis were observed with larazotide treatment.
Conclusions: LepR db/db mice exhibited increased albuminuria, kidney hypertrophy and increased intestinal permeability when compared to non-diabetic controls. However, larazotide treatment did not improve intestinal permeability. Notably, kidney injury markers were exacerbated in LepR db/db mice treated with larazotide. This finding has raised an intriguing question of whether larazotide is nephrotoxic in the setting of diabetes. Further investigations are required to unravel the underlying mechanisms of this observation.
Biography:
Amalia Khayyira is a second-year PhD student at Department of Diabetes, School of Translational Medicine, Monash University. She completed her Bachelor’s in Pharmacy and Master’s in Pharmaceutical Science at Universitas Indonesia. Her current research interest lies in targeting the gut in diabetic kidney disease. With a passion for translational medicine, she aspires to contribute significantly to the field of diabetes research.