Background: Diabetic nephropathy (DN) is a multifactorial and polygenic disease with nodular glomerulosclerosis (NGS) pathognomonic for diabetes and hypertension. Patients with type 2 diabetes and hypertension have characteristic renin-angiotensin system (RAS) gene polymorphisms.
Methods and results: In this retrospective cohort study, we correlated the presence of NGS with renal function, angiotensin-converting enzyme (ACE) genotypes (DD, DI, and II), angiotensinogen (AGT) genotypes (MM, MT, and TT) and immunohistochemical staining characteristics of RAS components in 847 patients and 172 consecutive autopsy cases with type 2 diabetes. T allele of AGT was associated with macroalbuminuria (P = 0.040). Multitude regression analysis revealed ACE insertion (I)/deletion (D) polymorphism as an independent determinant for estimated glomerular filtration rate (eGFR) less than 60 mL min(-1)·1.73 m(-2) (DD carriers: odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.08-11.07; DI carriers: OR = 3.51, 95% CI = 1.63-7.56). A significant association between NGS and eGFR less than 60 mL min(-1)·1.73 m(-2) also persisted after adjusting for nonlinear relationship (P < 0.001). In NGS patients, immunoreactivity of angiotensin I converting enzyme 2 (ACE2) significantly decreased in glomeruli with mesangial nodules compared with glomeruli without the mesangial nodules.
Conclusions: These data suggest associations of ACE D allele with glomerular filtration impairment, and NGS with glomerular ACE2 down-regulation and reduced glomerular filtration in Chinese patients with type 2 diabetes.
Keywords: Angiotensin I converting enzyme 2; Hypertension; Nodular glomerulosclerosis; Renin-angiotensin system; Type 2 diabetes.
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