title: Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus.
abstract: 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 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.
authors.affiliation: Ambulatory Nephrology Unit, Rambam Medical Center, Haifa 31096, Israel. f_nakhoul@rambam.health.gov.il
authors.forename: Farid M
authors.initials: FM
authors.lastname: Nakhoul
authors.forename: Rachel
authors.initials: R
authors.lastname: Miller-Lotan
authors.forename: Hoda
authors.initials: H
authors.lastname: Awad
authors.forename: Rabea
authors.initials: R
authors.lastname: Asleh
authors.forename: Kheir
authors.initials: K
authors.lastname: Jad
authors.forename: Nakhoul
authors.initials: N
authors.lastname: Nakhoul
authors.forename: Roy
authors.initials: R
authors.lastname: Asaf
authors.forename: Niroz
authors.initials: N
authors.lastname: Abu-Saleh
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Levy
mesh_terms: D000199:Actins / Q000378:metabolism; D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D006984:Hypertrophy; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010641:Phenotype; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000199:Actins; D000975:Antioxidants; D024141:Collagen Type IV; D006242:Haptoglobins; D014810:Vitamin E; D003404:Creatinine; D007501:Iron