Pyrazinoylguanidine attenuates diabetic nephropathy and prevents cataractogenesis in STZ-diabetic rats.

摘要

The overall hypothesis of the present studies is that in streptozotocin (STZ)-rats pyrazinoylguanidine (PZG) can attenuate long-term diabetic complications, specifically nephropathy and cataractogenesis. Diabetic nephropathy is a progressive disease afflicting both type I and type II diabetic patients, beginning with deranged renal hemodynamics and ending with renal failure. Diabetic patients develop cataracts earlier and with 5 times the frequency of the normal population. The STZ-induced diabetic rat model was chosen for several reasons: (1) STZ rats serve as models for both human diabetic nephropathy and cataracts; (2) In STZ rats, PZG exerts short-term beneficial metabolic effects on diabetes mellitus.;In human diabetic subjects, PZG has beneficial effects on the abnormal lipid and glucose metabolism associated with diabetes. Furthermore, PZG improves renal function in STZ-induced diabetic rats as well as human patients. With a priori knowledge of PZG's salutary effects in diabetes mellitus with respect to the associated renal and metabolic disturbances, STZ-induced diabetic rats served as models to test whether PZG can attenuate renal defects associated with long-term diabetes.;While testing the first hypothesis, a second hypothesis was developed: PZG can prevent cataract formation in STZ-induced diabetic rats. Pathogenic mechanisms underlying formation of diabetic cataracts are believed to be similar to those underlying nephropathy. Pathological changes in lens leading to cataracts are associated with hyperglycemia. Thus, antihyperglycemic effects of PZG may provide protection from cataractogenesis.;Experiments were conducted to test both hypotheses. Following previously described protocols, STZ was administered to rats intraperitoneally (45 mg/kg in 50 mM sodium citrate buffer). Once diabetes was established, as demonstrated by development of diabetic symptoms and repeated glucosuria by dipstick, treatment was begun. Diabetic rats were randomly divided and treated twice daily with one of the following: (1) vehicle (10 mg/kg saline, gavage); (2) pyrazinoylguanidine (35 mg/kg, gavage); (3) captopril (20 mg/kg, gavage); (4) hydrochlorothiazide (20 mg/kg, gavage): (5) insulin (Humulin, 7.5 IU per day, subcutaneous). Though cataracts appeared after 12 weeks, treatment was continued for 24 weeks to examine survival and temporal aspects of the evolution of diabetic nephropathy. PZG treatment of STZ-diabetic rats attenuated diabetic nephropathy, prevented cataract development, and improved longevity.