Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor ( BDKRB2 ) polymorphism with diabetic nephropathy

Purpose To determine whether ACE 2 I/D and BDKRB2 3 + 9/− 9 polymorphism causatively affect diabetic nephropathy progression Results STZ-induced metabolic disorder, as well as inflammatory responses, was significantly aggravated in ACE II-B2R 4 + 9 bp, ACE DD-B2R + 9 bp, or ACE DD-B2R − 9 bp diabetic mice but not ACE II-B2R − 9 bp, indicating the genetic susceptibility of ACE DD or B2R + 9 bp to diabetic nephropathy. Furthermore, ACE II-B2R + 9 bp, ACE DD-B2R + 9 bp, or ACE DD-B2R − 9 bp rather than ACE II-B2R − 9 bp, worsened renal performance and enhanced pathological alterations induced by STZ. Markedly elevated monocyte chemoattractant protein-1(MCP-1), podocin, osteopontin (OPN), transforming growth factor-β1 (TGF-β1), and reduced nephrin, podocin were also detected both in diabetic mice and podocytes under hyperglycemic conditions in response to ACE II-B2R + 9 bp, ACE DD-B2R + 9 bp, or ACE DD-B2R − 9 bp, versus ACE II-B2R − 9 bp. In addition, high glucose-induced mitochondrial oxidative stress and cell apoptosis were observably increased in response to ACE II-B2R + 9 bp, ACE DD-B2R + 9 bp, or ACE DD-B2R − 9 bp but not ACE II-B2R − 9 bp. Conclusions We provide first evidence indicating the causation between ACE DD or B2R + 9 bp genotype and the increased risk for diabetic nephropathy, broadening our horizon about the role of genetic modulators in this disease.