Plasminogen Activator Inhibitor-1 Deficiency Has Renal Benefits but Some Adverse Systemic Consequences in Diabetic Mice

Abstract

Background:Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are observed in patients with obesity, hypertension and diabetes, and several observations suggest that PAI-1 mediates diabetic vascular complications. Although increased intrarenal expression of PAI-1 is also a feature of diabetic nephropathy, evidence that PAI-1 plays a primary pathogenetic role in the renal pathology is lacking. Methods: This study was designed to investigate the renal effects of genetic PAI-1 deficiency in db/db mice with obesity, hyperinsulinemia and hyperglycemia. For comparison the effects of PAI-1 deficiency were also examined in a cohort of mice with insulin-deficient streptozotocin (STZ)-induced diabetes. The findings are reported for 4 study groups at 8 months of age: PAI-1+/+ controls, PAI-1+/+ diabetics, PAI-1–/– controls and PAI-1–/– diabetics. Results: PAI-1 deficiency had an unexpected negative impact on the db/db mice. Overall 33% of the diabetic mice died prematurely, and 63% of the db/db PAI-1–/– males had an obese body habitus but were runts. The final analyses were limited to the female db/db mice. Several nephropathy parameters were improved in the db/db PAI-1–/– group compared to the db/db PAI-1+/+ group including: albumin-to-creatinine ratios (57 ± 45 vs. 145 ± 71 µg/mg ×10), change in glomerular extracellular matrix (ECM) area (decrease of 10% compared to controls vs. an increase of 31%) and increased total kidney collagen (47% increased vs. 96% in the PAI-1+/+ diabetics). The serum glucose levels were 15–25% lower in the PAI-1–/– nondiabetic control groups and remained lower in the db/dbPAI-1–/– mice. The STZ study was performed in males. None of the mice developed a runted phenotype or died prematurely. After diabetes of 6 months’ duration changes in glomerular ECM area (–15 vs. +64%) and total kidney collagen (+8 vs. +40%) were lower in the PAI-1–/– mice compared to the PAI-1+/+ mice. The serum cholesterol levels were significantly lower in the PAI-1–/– mice, both controls (47 ± 3 vs. 53 ± 10 mg/dl) and diabetics (48 ± 3 vs. 74 ± 9 mg/dl). Conclusion: These data suggest a direct role for PAI-1 in renal matrix expansion and metabolic control in diabetes, but they also highlight important adverse outcomes that include male runting and premature death in mice with diabetes due to an inactive leptin receptor.