Diabetic Nephropathy in KK and KK-Ay Mice.

Okazaki, Masako; Saito, Yukako; Udaka, Yuko; Maruyama, Mine; Murakami, Hidetomo; Ota, Sumiko; Kikuchi, Takuya; Oguchi, Katsuji

doi:10.1538/expanim.51.191

Cited by 54 publications

(59 citation statements)

References 19 publications

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“…Albuminuria is a well known early sign of human DN. This clinical sign has already been confirmed in KK-A y mice [11,23], and the age-dependent gradual increase of the urinary albumin/creatinine ratio reported in these previous study also agreed well with the changes of glomerular sclerotic lesion scores seen in the present study.…”

Section: Discussionsupporting

confidence: 93%

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Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy

2010

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Abstract:The renin-angiotensin system plays a central role in the pathological mechanisms of diabetic nephropathy and is regulated by renal expression of cyclooxygenase-2 (COX-2). In the present study, the kidneys of diabetic KK-A y mice, a model of human type 2 diabetes, were investigated histologically and immunohistochemically at 8, 12, 16, and 20 weeks of age, and changes in renal lesions and expression of COX-2 and renin were evaluated quantitatively. Glomerular damage, characterized by expansion of mesangial matrices and nodular lesions, was observed in the kidneys of these mice. The glomerular sclerosis score gradually increased with age and was significantly higher than those of age-matched control C57BL/6 mice at 12, 16, and 20 weeks of age. Although mild tubulointerstitial damage was observed, there was no significant change in the interstitial fibrosis score. These findings were considered early diabetic nephropathy changes. COX-2-positive signals were consistently detected in the macula densa cells of the thick ascending limbs in all KK-A y mice, with a slightly higher score observed at 8 weeks of age. No COX-2-positive signals were detected in C57BL/6 mice. Renin-positive signals were commonly detected in the juxtaglomerular arterioles, and the scores in KK-A y mice increased at 16 weeks and decreased at 20 weeks of age. The present study demonstrated activation of renal COX-2 and renin expression in diabetic KK-A y mice at different stages. This finding suggests that these two enzymes contribute to the development and progression of diabetic nephropathy via different mechanisms.

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Section: Discussionsupporting

confidence: 93%

“…The DN phenotypes in KK-A y mice are more severe than those in the original KK mouse [23], and a recent study showed that DN in KK-A y mice resembled human DN, both histopathologically and immunohistochemically [11]. An interaction between hemodynamic and metabolic factors induces DN [28].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy

2010

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“…Many mouse models of diabetes have been established including type 1 diabetes due to streptozotocin (STZ) treatment and genetic models (e.g., C57BL/ 6-Ins2 Akita /J) (12)(13)(14). Models of type 2 diabetes include diet-induced and inherited deficiency in the leptin receptor (i.e., db/db) mice (15)(16)(17). However, nephropathy has been studied in only a limited number of strains, and none of these models develops renal lesions that fully resemble advanced human diabetic nephropathy (18).…”

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confidence: 99%

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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“…Okazaki et al (2002) reported that blood hemoglobin Al* Ievels were significantly correlated with urinary albumin excretion in KK-Ay mice. In this study, the mice excreted a significant amount of albumin in the urine; the amount was significantly smaller in the KK-Ay mice fed the 6-MSITC diet than in the controls.…”

Section: Discussionmentioning

confidence: 99%

6-Methylsulfinylhexyl Isothiocyanate, an Antioxidant Derived from Wasabia japonica MATUM, Ameliorates Diabetic Nephropathy in Type 2 Diabetic Mice

Fukuchi¹,

Kato²,

Okunishi³

et al. 2004

FSTR

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Many studies have examined the protective effects of antioxidative agents against diabetic nephropathy, using various models. 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) isolated from wasabi (Wasabiajaponica MATUM) induces glutathione S-transferase in vitro, thus 6-MSITC may act as an antioxidant in vivo. The aim of this study was to examine whether wasabi powder (WP) and 6-MSITC suppress oxidative stress in vivo and inhibit the impairment of renal function and diabetic nephropathy, using type 2 diabetic mice. KK-Ay type 2 diabetic mice were assigned to three groups (n = 10 each); control mice were fed normal chow (CRF-1) and two experimental groups were fed CRF-1 containing 0.5% WP or 0.03% 6-MSITC for 4 wk. Urine volume, urinary albumin excretion, and creatinine clearance were significantly lower in the 6-MSITC group than in the control group. There was statistically no difference in TBARS or other biomarkers of oxidative stress among the three groups. However, urinary 8-hydroxy-2'-deoxyguanosine (8-0HdG), one of the markers of oxidative stress tended to be lower in the 6-MSITC group than in the control group. In conclusion, the present results show that a sufficient supply of dietary 6-MSITC may prevent or delay renal dysfunction in diabetes by protecting against oxidative stress, and that dietary 6-MSITC may have beneficial effects on diabetic complications in type 2 diabetic mice.

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Diabetic Nephropathy in KK and KK-Ay Mice.

Cited by 54 publications

References 19 publications

Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy

Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy

Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

6-Methylsulfinylhexyl Isothiocyanate, an Antioxidant Derived from Wasabia japonica MATUM, Ameliorates Diabetic Nephropathy in Type 2 Diabetic Mice

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