الفهرس 
Introduction and Aim of WorkOnly 14 pages are availabe for public view
 |  | from | 230 |  |  |
| | | from | 230 | | |
Abstract
Diabetes is a leading cause of disability and mortality with devastating consequences. Diabetes is a major cause of renal dysfunction and damage with consequent renal redox imbalance, inflammatory, fibrotic and apoptotic responses.
Exenatide, GLP-1 agonist, and sitagliptin, DPP-4 inhibitor, are used for T2DM with nephroprotective properties. Moreover, mesenchymal stem cells are attractive tool in managing diabetes and its complications.
This study was conducted to investigate the ameliorative effects of incretin-based therapies on the diabetes-associated renal dysfunction and whether GLP-1 agonist or DPP-4 inhibitor can provide a superior beneficial effect on the renal complications in T2DM. In addition, we attempted to elucidate the underlying mechanisms involved in this setting .Moreover, the current study investigated and compared the proposed nephroprotective effect of MSCs alone against its combination with either EXE or SITA on DN rat model.
In this concern, we designed two aims to compare GLP-1 based therapies as nephroprotective agent against diabetes which was conducted in the first aim. The second aim elaborated the effect of combined therapy of MSCs with GLP-1 modulations on nephropathy induced in diabetic rats.
Adult male rats were initially divided into two groups, control and HFD/STZ-induced diabetes. Four weeks later after induction of diabetes, HFD/STZ-induced diabetic rats were further subdivided into groups; each consists of 10 rats, and was given the respective drug regimen for another four weeks.
Diabetic rats were administered the following drugs for 4 weeks: EXE (50 µg/kg/day, sc) and SITA (10 mg/kg/day, p.o). HFD/STZ-induced diabetes caused renal dysfunction which was confirmed by renal histopathological alterations, an increase in renal index and urinary ACR along with elevation of serum Cr and urea in diabetic rats compared to the control group. Moreover, there were disturbances in oxidative stress parameters, MDA and CAT, and up-regulation of inflammatory marker (TNF-α), pro- fibrotic marker (TGF-β) and apoptotic marker (C-caspase) in diabetic kidney tissues. Apart from ameliorating glucose intolerance and insulin resistance, both investigated drugs were found to be the same as protective therapy in terms of enhancing kidney function and suppressing renal oxidative stress, inflammation, fibrosis and apoptosis in diabetic rats. The results of the present study clearly demonstrated that rats treated with MSCs (1×107 cells, single dose, iv) produced a significant amelioration of renal dysfunction and renal histopathological disturbances. Of interest, MSCs-treated group suppressed oxidative stress as evident by attenuated renal lipid peroxidation product, MDA content, and elevated the activity of antioxidant enzyme, CAT, along with downregulated renal TNF-α, TGF-β and C-caspase protein expressions. It is worth noting that rats treated with MSCs with either SITA or EXE exhibited a marked decrease in the kidney weight index, serum level of renal function biomarkers (Cr and urea), urinary ACR, MDA level with significant increase in the CAT activity. Moreover, both combination regimens showed further down-regulation in renal protein expression of TNF-α, TGF-β and C-caspase. Furthermore, the microscopic examination revealed that improvement in histopathological changes was more profound in groups treated with combined regimens compared to their monotherapy.
In conclusion, the present findings demonstrated that both incretin-modulated therapies ameliorated early DN with similar ameliorative effect suggesting that glucose control is not the main mechanism. These drugs may enhance kidney function through modulating dyslipidemia, anti-oxidative, anti-inflammatory, anti-fibrotic and anti-apoptitic actions. Moreover, the dual therapy of either EXE with stem cells or SITA with stem cells provided a marked additional protection against diabetes-induced kidney injury. This potentiation of the renoprotective effect of MSCs by EXE or SITA treatment can be possibly explained by the improvement of MSCs viability, glycolipid intolerance alongside anti-oxidative, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Therefore, incretin mimetic agents may be useful tools to enhance the biological functions of MSCs in diabetic renal complications. This invites clinical studies to evaluate the potential impact of this combined regimen in patients with DN.