Kidney Disease in KK Mice: Structural, Biochemical and Functional Relationships

Reddi, Alluru S.; Wehner, H.; Khan, M. Y.; Camerini-Dávalos, Rafael A.

doi:10.1007/978-1-4684-5616-5_17

Cited by 4 publications

(3 citation statements)

References 3 publications

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“…The KK strain has previously been proposed to represent a model of diabetic nephropathy (17,(41)(42)(43). The present finding of moderate albuminuria in nondiabetic KK/HlJ mice (Fig.…”

Section: Diabetes Vol 54 September 2005supporting

confidence: 61%

Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

et al. 2005

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Differential susceptibility to diabetic nephropathy has been observed in humans, but it has not been well defined in inbred strains of mice. The present studies characterized the severity of diabetic nephropathy in six inbred mouse strains including C57BL/6J, DBA/2J, FVB/NJ, MRL/MpJ, A/J, and KK/HlJ mice. Diabetes mellitus was induced using low-dose streptozotocin injection. Progression of renal injury was evaluated by serial measurements of urinary albumin excretion, glomerular filtration rate (GFR), and terminal assessment of renal morphology over 25 weeks. Despite comparable levels of hyperglycemia, urinary albumin excretion and renal histopathological changes were dramatically different among strains. DBA/2J and KK/HlJ mice developed significantly more albuminuria than C57BL/6J, MRL/MpJ, and A/J mice. Severe glomerular mesangial expansion, nodular glomerulosclerosis, and arteriolar hyalinosis were observed in diabetic DBA/2J and KK/HlJ mice. Glomerular hyperfiltration was observed in all diabetic strains studied except A/J. The significant decline in GFR was not evident over the 25-week period of study, but diabetic DBA/2J mice exhibited a tendency for GFR to decline. Taken together, these results indicate that differential susceptibility to diabetic nephropathy exists in inbred mice. DBA/2J and KK/HlJ mice are more prone to diabetic nephropathy, whereas the most widely used C57BL/6J mice are relatively resistant to development of diabetic nephropathy. Diabetes 54:2628 -2637, 2005

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“…The KK strain has previously been proposed to represent a model of diabetic nephropathy (17,(41)(42)(43). The present finding of moderate albuminuria in nondiabetic KK/HlJ mice (Fig.…”

Section: Diabetes Vol 54 September 2005supporting

confidence: 61%

Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

et al. 2005

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“…Although exhibiting only mild insulin resistance, the KK mouse seems to be predisposed to development of renal lesions very reminiscent of DN (167,168). These mice were originally established from inbreeding a Japanese mouse by Kondo (169).…”

Section: Kk Micementioning

confidence: 99%

Mouse Models of Diabetic Nephropathy

Breyer¹,

Böttinger²,

Brosius³

et al. 2005

Journal of the American Society of Nephrology

477

516

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Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.J (1), with costs for care of these patients projected to be $12 billion/yr by 2010 (1). Despite the high prevalence of DN, only 20 to 40% of all diabetic patients are prone to developing kidney failure, and family-based studies suggest that a significant genetic component confers risk for DN (2-4). Studies of diabetic mice suggest that, like people, mice exhibit differential susceptibility to diabetes and renal and cardiovascular diseases (5-7). In mice, identification of a strain that is prone to disease provides the relevant discriminator rather than identification of an individual who is at risk for diabetic complications. However, in contrast to people, each inbred mouse strain represents a genetically homogeneous and readily replenished resource that is amenable to repeated experimental study.Biomedical experimentation in mice affords significant advantages over experimentation in other species. These advantages include the development of diverse and unique genetic resources, including completion of a detailed map of murine genomic sequence that is freely available through the internet, as well as Ͼ450 inbred strains of mice that have been generated over the past century, with each strain genetically being homogeneous and offering a unique array of phenotypes (8,9). The availability of murine embryonic stem cells has also provided the ability to disrupt the expression and function of specific preselected genes (10 -12). Finally, repositories of mice that bear multiple mutations that alter function in each known gene are gradually being assembled (13-15). These unique resources have the potential to significantly facilitate studies into the pathogenesis of disease in mice. Through the use of the unique genetic reagents that are available in mice (including knockouts and transgenics), the identification of a robust mouse model of DN should significantly facilitate understanding of the underlying genetic mechanisms that contribute to the development of DN in people as well as in mice. Establishment of a valid mouse model of DN should also facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans. Workin...

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“…The inbred KK/Ta mouse strain, established in Japan as a diabetic strain, spontaneously exhibits type 2 diabetes associated with fasting hyperglycemia, glucose intolerance, hyperinsulinemia, mild obesity, dyslipidemia, and proteinuria 15 . Since KK/Ta mice spontaneously develop renal lesions closely resembling those in human diabetic nephropathy, 16 we carried out a genome‐wide linkage analysis of KK/Ta alleles contributing to type 2 diabetes and related phenotypes such as albuminuria and obesity using 103 microsatellite markers in 208 KK/Ta × (BALB/c × KK/Ta) F1 backcross progeny 17,18 . We identified three major chromosomal intervals significantly contributing to glucose metabolism: one quantitative trait locus for impaired glucose tolerance on chromosome (Chr) 6 and two loci for fasting blood glucose levels on Chr 12 and 15.…”

Section: Susceptibility Loci Contributing To Type 2 Diabetic Nephropamentioning

confidence: 99%

Genetic susceptibility to type 2 diabetic nephropathy in human and animal models

et al. 2005

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Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Japan, Western Europe, and the United States. Mega studies such as Diabetes Control and Complication Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) clarified that poor glycemic and blood pressure control are undoubtedly involved in the development of nephropathy. However, these factors are not sufficient to predict which diabetic patients will develop renal disease, because not all patients with poor glycemic and blood pressure control develop renal disease. Since ethnic variations and familial clustering of diabetic nephropathy have been observed, genetic factors might contribute to susceptibility to this disease. Several methods such as (genome wide) association studies, sib-pair analysis, and quantitative trait loci (QTLs) analysis are available to examine polygenic diseases. However, no mutations that could explain the majority of nephropathy cases have been identified so far. The development of most diabetic nephropathy might be explained by the polygenic effect (i.e. many minor gene-gene interactions might be very important in the development of nephropathy). Identification of candidate genes of nephropathy enables targeting of therapy in patients at risk and development of novel therapeutic agents.

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Kidney Disease in KK Mice: Structural, Biochemical and Functional Relationships

Cited by 4 publications

References 3 publications

Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

Mouse Models of Diabetic Nephropathy

Genetic susceptibility to type 2 diabetic nephropathy in human and animal models

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