A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy.

A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Research Abstract Details 

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A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Abstract Text:

Elena E Tchekneva,Eugene M Rinchik,Dina Polosukhina,Linda S Davis,Veronika Kadkina,Yassir Mohamed,Steve R Dunn,Kumar Sharma,Zhonghua Qi,Agnes B Fogo,Matthew D Breyer,

Diabetic nephropathy (DN) is a late diabetic complication that comprises progressively increasing albuminuria, declining GFR, and increased cardiovascular risk. Only a minority of patients with diabetes (25 to 40%) develop nephropathy, and there is evidence that heritable genetic factors predispose these "at-risk" individuals to DN. Comparing variability among inbred mouse strains with respect to a specific phenotype can model interhuman variability, and each strain represents a genetically homogeneous system with a defined risk for nephropathy. C57BL/6 mice, which are relatively resistant to DN, were mutagenized using N-ethyl-N-nitrosourea and screened for mutants that developed excess albuminuria on a sensitizing type 1 diabetic background contributed by the dominant Akita mutation in insulin-2 gene (Ins2(Akita)). Two of 375 diabetic G1 founders were found to exhibit albumin excretion rates persistently 10-fold greater than albumin excretion rates in nonmutagenized Ins2(Akita) controls. This albuminuria trait was heritable and transmitted to approximately 50% of Ins2(Akita) G2 and G3 progeny, consistent with a simple, dominantly inherited trait, but was never observed in nondiabetic offspring. During the course of 1 yr, albuminuric Ins2(Akita) G2 and G3 progeny developed reduced inulin clearance with elevated blood urea nitrogen and plasma creatinine. Glomerular histology revealed mesangial expansion, and glomerular basement membrane thickening as determined by electron microscopy was enhanced in diabetic mutant kidneys. Hereditary albuminuric N-ethyl-N-nitrosourea-induced mutants were redesignated as Nphrp1 (nephropathy1) and Nphrp2 (nephropathy2) mice for two generated lines. These novel mutants provide new, robust mouse models of DN and should help to elucidate the underlying genetic basis of predisposition to DN.

A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Publishing Authors By Initials

EE Tchekneva,EM Rinchik,D Polosukhina,LS Davis,V Kadkina,Y Mohamed,SR Dunn,K Sharma,Z Qi,AB Fogo,MD Breyer,

For similar investigative techniques: epidemiologic methods: statistics as topic: sensitivity and specificity research abstracts see: investigative techniques: epidemiologic methods: statistics as topic: sensitivity and specificity research

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A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of the American Society of Nephrology : JA

VOLUME: 18

Page Numbers: 103-12

Journal Abbreviation: J. Am. Soc. Nephrol.

ISSN: 1046-6673

DAY: 6

MONTH: 12

YEAR: 2006

A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9013836

A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Keywords Mesh Terms:

KEYWORDS: Sensitivity and Specificity

MESH TERMS: toxicity

Chemical & Substance for Abstract: A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. Information

Substance Name: Ethylnitrosourea

Registry Number: 759-73-9

Grant and Affiliation Information for A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy.

AFFILIATION: Division of Nephrology and Hypertension, Vanderbilt University Medical Center, 21st Avenue S. at Garland, Nashville, TN 37232, USA. elena.tchekneva@vanderbilt.edu

Country: United States

AGENCY: United States NIDDK

GRANT: U01 DK061018

ACRONYM: DK

MEDLINETA: J Am Soc Nephrol

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