Effect of combined therapy of mesenchymal stem cells with GLP-1 receptor agonist, exenatide, on early-onset nephropathy induced in diabetic rats

Eur J Pharmacol. 2021 Feb 5:892:173721. doi: 10.1016/j.ejphar.2020.173721. Epub 2020 Nov 4.

Abstract

Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions for its recession remains unsatisfactory. Mesenchymal stem cells (MSCs) hold an attractive source for renovating injured tissues. Unfortunately, limited self-renewal and migration capacity of MSCs after transplantation hinder their clinical applicability which demands a new policy for enhancing their biological functions. This study aimed to investigate whether the renoprotective potential of adipose-derived MSCs (ADMSCs) in diabetic rats could be promoted by exenatide, a glucagon-like peptide-1 (GLP-1) analogue. These effects were studied in type 2 diabetes mellitus rats which were administrated ADMSCs, exenatide or their combination four weeks post-induction. Four weeks later, renal function parameters were evaluated. To address the possible underlying mechanisms, parameters indicating glycolipid metabolism tolerance and oxidative stress biomarkers were assessed in renal tissues alongside evaluation of protein expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and cleaved caspase-3. The results showed that the combined therapy had superior renoprotective effect as evident by significant improvement in kidney function and renal architecture changes through rebalancing of inflammatory, fibrotic and apoptotic markers. Based on these outcomes, ADMSCs with exenatide were supposed to effectively ameliorate diabetic renal dysfunction compared to ADMSCs solely, presenting a promise therapy for diabetic nephropathy with further clinical studies warranted to validate this effect.

Keywords: Adipose-derived mesenchymal stem cell; Diabetic nephropathy; Exenatide.

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / therapy*
  • Diabetes Mellitus, Type 2 / chemically induced
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / therapy*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / therapy*
  • Exenatide / pharmacology*
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / metabolism
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Wistar
  • Streptozocin
  • Subcutaneous Fat / cytology
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Blood Glucose
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Streptozocin
  • Exenatide
  • Casp3 protein, rat
  • Caspase 3