Molecular mechanisms underlying the attenuation of diabetes-induced renal injuries by mesenchymal stem cells -

Abstract

Background: Diabetic nephropathy (DN) is one of the major complications of diabetes. It is characterized by morphological and functional renal alterations such as tubulointerstitial fibrosis, glomerulosclerosis and protenuria ultimately leading to end stage renal disease. Diabetes, among several pathological conditions, alters the redox balance causing modifications in the DNA, the proteins and the antioxidant system leading to oxidative stress. Aims: An emerging body of studies has shown that stem cells have the potential to improve acute tubular injury recovery and glomerular repair. However, the mechanism of repair of MSCs is not yet identified. The present study aims to determine the effect of MSCs treatment on oxidative stress, specifically on ROS production and to investigate the mechanistic pathway by which MSCs attenuate renal injury. Methods: 4 weeks streptozotocin-induced diabetic rats received weekly injections of 1x106 cell MSCs intravenously, while the control and diabetic groups received weekly injections of media. After eight weeks of treatment, physical, histological and biochemical parameters and kidney function were measured. Dihydroethidium (DHE) was used to assess intracellular ROS production levels. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was performed to determine mRNA levels of fibronectin and collagen IV, Nox4, CYP4A and CYP2C11 and TGF-β. The histological alterations were measured using different histochemical stains including HandE, PAS and Masson Trichrome. Results: MSCs treatment had no effect on the blood glucose levels yet restored normal urinary albumin excretion levels markers of diabetic kidney injury, i.e. glomerulosclerosis detected by periodic acid Schiff (PAS) stain, tubulointerstitial fibrosis revealed by Masson Trichrome stain and expression of fibronectin, laminin and collagen IV in MSCs treated rats were reversed in rats treated with MSCs compared to STZ-diabetic rats. Oxidative stress was also decreased by the normalized levels of Nox4, CYP