Age-related expression of renal thrombospondin 1 mRNA in F344 rats: Resemblance to diabetes-induced expression in obese Zucker rats

Age-related increases occurred in renal thrombospondin 1 (TSP1) mRNA in F34 4 rats, resembling diabetes-induced TSP1 mRNA in the obese Zucker rat. TSP1 mRNA was 3.5-fold higher in 24-month-old than in 3-month-old F344 rats. TS P1 mRNA increased similarly in 5-month-old obese Zucker rats as compard wit h lean littermates and correlated positively with the extent of proteinuria (r = 0.71). In situ hybridization identified elevated TSP1 mRNA levels in epithelial cells of distended tubules as well as in interstitium near dilat ed tubules of both 24-month-old F344 rats and 5-month-old obese Zucker rats . Furthermore, thrombin increased TSP1 mRNA in mesangial and epithelial cel ls in culture, indicating that thrombin may contribute to elevated TSP1 exp ression in renal disease. Thrombin increased TSP1 mRNA within 30 min after treatment which required de novo synthesis of protein. The thrombin recepto r tethered ligand peptide, SFLLRN, increased TSP1 mRNA, indicating that the thrombin-induced increase in TSP1 mRNA was due to direct thrombin receptor (PAR1) stimulation. These results show that increased TSP1 mRNA levels are a component of interstitial fibrosis seen in aged and diabetic kidneys and suggest that similar pathological changes occur in kidneys of aging and di abetic rats.