Diabetes-induced renal injury in rats is attenuated by suramin.
Progression of hyperglycemia-induced renal injury is a contributing factor for diabetic nephropathy (DN)-induced end-stage renal disease (ESRD), and development of novel therapeutic strategies that act early to prevent progression of DN and ESRD are important. We examined the efficacy and mechanism(s) of suramin on hyperglycemia-induced renal injury before development of overt histological damage. Two groups of male Sprague-Dawley rats received streptozotocin (STZ) and one group received saline. Three weeks later, one STZ group received suramin (10 mg/kg). All animals were euthanized 1 week later (4 weeks). Although there was a decrease in creatinine clearance between control and STZ ± suramin rats, there was no difference in creatinine clearance between STZ rats ± suramin intervention. Liquid chromatography-tandem mass spectroscopy-based analysis revealed increases in urinary proteins that are early indicators of DN (e.g., cystatin C, clusterin, cathepsin B, retinol binding protein 4, and peroxiredoxin-1) in the STZ group, which were blocked by suramin. Endothelial intracellular adhesion molecule-1 (ICAM-1) activation, leukocyte infiltration, and inflammation; transforming growth factor-β1 (TGF-β1) signaling; TGF-β1/SMAD-3-activated fibrogenic markers fibronectin-1, α-smooth muscle actin, and collagen 1A2; activation of proinflammatory and profibrotic transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription factor-3 (STAT-3), respectively, were all increased in STZ rats and suramin blocked these changes. In conclusion, delayed administration of suramin attenuated 1) urinary markers of DN, 2) inflammation by blocking NF-κB activation and ICAM-1-mediated leukocyte infiltration, and 3) fibrosis by blocking STAT-3 and TGF-β1/SMAD-3 signaling. These results support the potential use of suramin in DN.
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Midhun C
MC
Korrapati
Brooke E
BE
Shaner
Benjamin A
BA
Neely
Joseph L
JL
Alge
John M
JM
Arthur
Rick G
RG
Schnellmann
D000818:Animals; D015415:Biomarkers / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000652:urine*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000652:urine*; D018799:Intercellular Adhesion Molecule-1 / Q000652:urine; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000209:etiology / Q000652:urine; D008297:Male; D016328:NF-kappa B / Q000652:urine; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013498:Suramin / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000652:urine; D016896:Treatment Outcome
D015415:Biomarkers; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D013498:Suramin