| Authors |
Tchekneva EE, Rinchik EM, Polosukhina D, Davis LS, Kadkina V, Mohamed Y, Dunn
SR, Sharma K, Qi Z, Fogo AB, Breyer MD
|
| Submitted By |
Muhammad Abdul-Ghani on 1/9/2006 |
| Status |
Published |
| Journal |
Journal of the American Society of Nephrology : JASN |
| Year |
2007 |
| Date Published |
1/1/2007 |
| Volume : Pages |
18 : 103 - 112 |
| PubMed Reference |
17151334 |
| Abstract |
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.
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