title: Genetic modulation of diabetic nephropathy among mouse strains with Ins2 Akita mutation.
abstract: Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end-stage renal disease. DN is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty-eight Akita strains were generated by breeding this panel to DBA/2.Akita mice. Male F1 diabetic and nondiabetic littermates were evaluated for DN-related traits. Urine albumin-to-creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains. For most Akita strains, ACR values increased 2- to 6-fold over euglycemic control values. However, six strains exhibited changes in ACR exceeding 10-fold with two strains (NOD/ShiLt and CBA) showing 50- to 83- fold increases. These increases are larger than previously reported among available DN mouse models establishing these strains as useful for additional studies of renal function. ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte-stress contributed to reduced kidney function assessed by ACR. Although large changes were seen for ACRs, severe nephropathology was absent. However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN. Our results define the range of DN phenotypes that occur among common inbred strains of mice.
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Davis
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: McMillen
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Schaeffer
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Qi
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Parisa N
authors.initials: PN
authors.lastname: Mazandarani
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Roshanak
authors.initials: R
authors.lastname: Alialy
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Renée C
authors.initials: RC
authors.lastname: LeBoeuf
keywords: Akita; Albuminuria; Animal models; Diabetic nephropathy; Genetics