SRT1720 Administration Attenuates Albuminuria and Renal Fibrosis on Adriamycin‐Induced Glomerulosclerosis

Abstract

The focal segmental glomerulosclerosis (FSGS) is the leading cause of progression of chronic kidney disease (CKD) and its responsible for the increasing number of cases of dialysis and kidney transplants worldwide. The lack of knowledge about the mechanisms underlying the progression of FSGS makes it difficult to develop therapeutic approaches with regarding the proteinuria and CKD progression. The aim of the study is to investigate the role of SIRT1 on FSGS induced by adriamycin, focusing on renoprotective responses. For this we used a synthetic SIRT1 agonist, the SRT1720. Male Balb/c mice aged 5 weeks were organized into two treatment groups: 48h and 14 days, being thus distributed in four experimental conditions: control (vehicle), adriamycin (ADR, 10 mg/kg), treated with SRT1720 (20 mg/kg/day) and treated with ADR+SRT1720. After the treatment, physiological parameters such as body weight, renal weight, weight gain, and plasma parameters such as creatinine, urea and osmolarity were evaluated. The glomerulosclerosis index was assessed by quantifying the renal sections stained with periodic acid-schiff (PAS). Urinary albumin was detected after staining the SDS-polyacrylamide gel. For the 48h group, the expression of mRNA was performed by quantitative real time PCR. For the 14-day group, GRP78, claudin-1, phospho eIF2αSer51 and phospho AMPKαThr172 protein expression were evaluated by immunoblotting. Type-IV collagen and nephrin staining were verified by immunofluorescence using confocal microscopy. The results indicate that for the ADR 48h group there was a decrease in final body weight, renal weight and an increase in plasma creatinine concentration compared to the control group. Administration of SRT1720 mitigates part of these effects, improving renal function. Our data indicate that although there is no positive stain for glomerulosclerosis in PAS or differences in the gene expression of Kim1, Tnf and Nphs1, the animals already have significant albuminuria within 48 hours after ADR administration in comparison to control, group, which suggests an initial damage on glomerular ultrafiltration barrier. Regarding the 14-day group, a decrease in final weight, an increase in renal weight, an increase in plasma creatinine, a significant increase in urinary albumin and the glomerulosclerosis index for ADR animals are observed, and this effect was clearly reversed by administration of SRT1720. There were no changes in creatinine clearance between groups after 14 days of treatment, despite an increase in urinary flow for the ADR + SRT1720 group. Although there were no significant differences on GRP78, phospho eIF2αSer51 or claudin-1 protein expression, the ADR+SRT1720 group showed an increase on phospho AMPKαThr172. Type IV collagen deposition was observed in ADR mice, as well as an important reduction in glomerular nephrin marking. These effects were partially reversed by the administration of the SRT1720. In conclusion, our data indicate that SRT1720 administration, a synthetic SIRT1 agonist, can improve renal function, mainly by partially preserving the glomerular ultrafiltration barrier and inhibiting renal fibrosis.