MO612: Relationship of Renal Timp-1, Stat3 and Inflammatory Factors in Diabetes

Abstract

Abstract BACKGROUND AND AIMS The balance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMP) is disrupted in diabetic nephropathy and renal TIMP-1 overexpression is observed in both animal experimental models and human biopsies. The STAT3 transcription factor participates in several inflammatory pathways; however, its interaction with TIMP-1 in diabetes remains unknown. We aimed to investigate the progression of nephropathy and its relationship to renal STAT3 activation in type-1 diabetic TIMP-1 knock-out (KO) mice. METHOD Diabetes was induced in 6-week-old male TIMP-1 KO (DM-KO, n = 8) and C57Bl6 wild type (DM, n = 5) mice by intraperitoneal streptozotocin injections (50 mg/kg/day for 5 days). Control mice (CTL, n = 6) received citrate buffer injections. Eight weeks after onset of diabetes blood and urine chemistries, renal histology, renal mRNA and protein expression were assessed. Statistical significance was evaluated using Kruskal–Wallis test and Tukey post-hoc analysis. RESULTS Despite similar hyperglycemia, DM-KO mice developed significantly less proteinuria (P <0.01) and histologically milder glomerulosclerosis and tubular damage as compared with wild type DM mice. Kidneys of DM mice depicted 4-fold STAT3 phosphorylation, but DM-KO kidneys had similar values as CTL nondiabetic controls. DM kidneys also showed 20-fold CCL2, 10-fold C3 and 2.5-fold C4 overexpression, which in DM-KO kidneys remained all near control (CTL) levels. CONCLUSION Based on our results, we conclude that TIMP-1 influences the progression of diabetic kidney disease in mice not solely through the inhibition of MMP-s, but also by influencing the extent of renal inflammation via STAT3 phosphorylation. Therefore, TIMP-1 might emerge as promising future therapeutic target. FUNDING Hungarian Academy of Sciences BO/00 304/20/5, ÚNKP-21–5-SE-1.