Background: Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of fibrinolytic pathway and extracellular matrix (ECM) turnover. Because diabetic nephropathy is characterized by the presence of basement membrane thickening and mesangial expansion, we examined the role of PAI-1 gene polymorphisms in the development of type 2 diabetic nephropathy. Evidence also suggested that the PA/plasmin system and the renin-angiotensin system (RAS) interact together to affect the risk of fibrosis and thrombosis. Hence, we also studied the synergistic effect between PAI-1 and angiotensin-converting enzyme (ACE) gene polymorphisms.
Methods: The PAI-1 and ACE (D/I) gene polymorphisms were examined in a cohort of Chinese type 2 diabetic patients who had diabetes for an average of 14 years. These patients were sex and age matched. Group A (N = 46) consisted of patients without diabetic nephropathy (normoalbuminuric with creatinine <120 micromol/L), and group B (N = 95) was with diabetic nephropathy (with albuminuria or renal impairment, including patients on dialysis).
Results: Patients with type 2 diabetic nephropathy had a higher frequency of PAI-1 (4G/4G) genotypes than those without nephropathy [4G/4G:4G/5G:5G/5G = 41:38:21 (%) vs. 15:65:20(%), P = 0.005]. Diabetic patients with coexistence of PAI-1 4G/4G genotype and ACE D alleles had a higher incidence of diabetic nephropathy (22 vs. 7%, P = 0.012) than those with other combinations of genotypes. Multivariate logistic regression analysis showed that PAI-1 4G/4G (P = 0.01) and the prevalence of hypertension (P < 0.0001) are independent risk factors of development of type 2 diabetic nephropathy.
Conclusions: These results suggest that the PAI-1 4G/4G genotype is associated with an increased risk for type 2 diabetic nephropathy in Chinese patients, which is an independent risk factor for the development of nephropathy. The PAI-1 4G/4G genotype also exhibits a synergistic effect with the ACE D allele on development of diabetic nephropathy.