The role of the hydrogen sulfide system in the nephroprotection mechanisms of metformin action on streptozotocin-induced diabetes

Abstract

Summary. Diabetic nephropathy is a common microvascular complication of diabetes mellitus (DM), which develops in approximately 40 % of patients with type 2 DM. For the treatment of diabetic kidney damage, metformin is widely used – a drug that controls blood glucose levels and has proven nephroprotective properties. In present time, the role of the H₂S system in the mechanisms of the nephroprotective activity of metformin has not been investigated.

The aim of the study – to assess the influence of modulators of H₂S exchange on the main mechanisms of nephroprotective action of metformin in experimental diabetes.

Materials and Methods. Experimental studies were conducted on 75 white non-linear male rats, which were divided into five groups: group 1 – control; group 2 – animals with experimental diabetes, which was initiated by a single intraperitoneal injection of streptozotocin (40 mg/kg of weight); group 3 – animals with experimental diabetes, which were treated with metformin (500 mg/kg/day, intragastrically) from the 3rd to the 28th day; group 4 – animals with DM, which were administered metformin together with NaHS (56 μmol/kg/day, intragastrically); group 5 – animals with diabetes, to which metformin was administered together with propargylglycine (PPG, 442 μmol/kg/day, intragastrically). Glucose content was determined in peripheral blood, and the level of H₂S, galectin-3, caspase-3, IL-1β, malondialdehyde (MDA), protein carbonyl groups (PCG), NADPH oxidase and superoxide dismutase (SOD) activity was assessed in the supernatant of the kidney homogenate.

Results. It was established that the use of metformin in experimental diabetes showed antioxidant (the level of MDA and PCG decreased by 24.7–27.4%, p˂0.001), anti-inflammatory (the level of IL-1β decreased by 25.3 %,  p˂ 0.001), antiapoptotic (the level of caspase-3 decreased by 36.1 %, p˂0.001) and antifibrogenic (the level of galectin decreased by 48.4 %, p˂0.001) activity in the kidneys, which was associated with an increase (by 27.9 %,  p˂ 0.001) of H₂S level (│r_s│ = 0.59–0.75, p˂0.01). The use of H₂S modulators modified the nephroprotective properties of metformin in diabetes condition. Administration of NaHS (the hydrogen sulfide donor) potentiated the protective effect of metformin in the kidneys: the levels of galectin-3, caspase-3, IL-1β, MDA, and PCG in the kidneys were significantly lower, respectively, by 18–37 % (p˂0.001) than in animals that received only metformin. At the same time, the use of the PPG (hydrogen sulfide synthesis inhibitor) probably reduced metformin protective activity in the kidney.

Conclusions. The conducted studies proved the important role of the H₂S system in the implementation of anti-inflammatory, anti-fibrogenic, anti-apoptotic and antioxidant effects of metformin in the kidneys in diabetes condition. Along with this, the obtained results pathogenetically substantiate the expediency of H₂S donors using to potentiate the nephroprotective properties of metformin.