Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus

Farid M. Nakhoul, Rachel Miller-Lotan, Hoda Awad, Rabea Asleh, Kheir Jad, Nakhoul Nakhoul, Roy Asaf, Niroz Abu-Saleh, Andrew P. Levy
2009 AJP - Renal Physiology  
Nakhoul FM, Miller-Lotan R, Awad H, Asleh R, Jad K, Nakhoul N, Asaf R, Abu-Saleh N, Levy AP. Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus. Polymorphic loci regulating oxidative stress are potential susceptibility genes for diabetic nephropathy (DN). Haptoglobin (Hp) is an antioxidant protein which serves to protect against oxidative stress induced by extracorpuscular hemoglobin. There are two
more » ... There are two alleles at the Hp locus, 1 and 2. The Hp 1 protein is a superior antioxidant to the Hp 2 protein. The Hp 2 allele has been associated with increased prevalence of DN and appears to be associated with a more rapid progression to end-stage renal disease. We sought to recapitulate this association between Hp genotype and DN in mice genetically modified at the Hp locus. We assessed morphometric, histologic, and functional parameters involved in the development and progression of DN in mice with diabetes mellitus (DM) with either the Hp 2-2 or Hp 1-1 genotype. Morphometric analysis demonstrated that glomerular and proximal tubular hypertrophy were significantly increased in Hp 2-2 DM mice. Histological analysis demonstrated that Hp 2-2 DM mice had significantly more collagen type IV, smooth muscle actin, and increased renal iron deposition. Studies of renal function demonstrated creatinine clearance time and albuminuria were increased in Hp 2-2 DM mice. Vitamin E provided significant protection against the development of functional and histological features characteristic of DN to Hp 2-2 DM but not to Hp 1-1 DM mice. These studies serve to strengthen the association between the Hp 2-2 genotype and diabetic renal disease and suggest a pharmacogenomic interaction may exist between the Hp genotype and vitamin E. diabetic nephropathy; hyperglycemia APPROXIMATELY ONE-THIRD of all patients with diabetes mellitus (DM) develop end-stage renal disease (ESRD) necessitating renal replacement therapy within 25 years of DM onset (20, 37, 38, 40) . Long-term prospective and interventional studies have clearly demonstrated that the risk of developing diabetic nephropathy (DN) is directly related to exposure to hyperglycemia (7). However, family studies have clearly demonstrated that hyperglycemia is a necessary but not sufficient condition for the development of DN. Several lines of evidence have supported the concept that there exist polymorphic genetic loci which determine susceptibility to DN
doi:10.1152/ajprenal.90655.2008 pmid:19176700 fatcat:kwaovmma4rggzbcaw75cosskiu