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 DBA-akita Ins2Akita We have  the  insulin 2 Akita (Ins2Akita) mice on the DBA background (2). Ins2Akita are a recently described mouse mutant model of type I diabetes mellitus as a result of selective pancreatic ß-cell toxicity and depletion resulting from misfolding of insulin2. Mice heterozygous for the Akita spontaneous mutation (Ins2Akita) are viable and fertile; hyperglycemia, hypoinsulinemia, polydipsia, and polyuria begin around 3-4 weeks of age. Studies carried out by the Animal Models of Diabetic Complications Consortium (AMDCC) indicated that the DBA/2J strain is especially prone to develop diabetic nephropathic complications. Therefore, the advantage of this model of type I diabetes is the early onset, progressive functional and structural glomerular injury (2) and the fact that diabetes develops spontaneously.

In addition, since we previously found that streptozotduced diabetic glomerular injury is significantly accelerated in integrin α1KO mice on the Balb/c background (3), we have backcrossed the Ins2Akita mouse onto the Balb/c background and further crossed it with the integrin α1KO Balb/c mice. We have successfully generated wild type and integrin α1KO mice carrying both of the ins2 genes (referred to as α1WT/AkitaKO and α1KO/ AkitaKO mice.  Of interest, glomeruli from four month old α1KO/AkitaKO diabetic mice show increased glomerular damage and increased collagen IV deposition compared to their α1WT/AkitaKO diabetic counterparts (see Figure). In addition, more albuminuria is observed in the α1KO/AkitaKO mice. Therefore, this model represents an additional model of accelerated type I diabetic nephropathy.

Publications for Akita mice (2)

Zent R, Yan X, Su Y, Hudson BG, Borza DB, Moeckel GW, Qi Z, Sado Y, Breyer MD, Voziyan P, Pozzi A. Glomerular injury is exacerbated in diabetic integrin alpha1-null mice. Kidney Int (2006) 70:460-70
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Excessive glomerular collagen IV and reactive oxygen species (ROS) production are key factors in the development of diabetic nephropathy. Integrin alpha1beta1, the major collagen IV receptor, dowregulates collagen IV and ROS production, suggesting this integrin might determine the severity of diabetic nephropathy. To test this possibility, wild-type and integrin alpha1-null mice were rendered diabetic with streptozotocin (STZ) (100 mg/kg single intraperitoneal injection), after which glomerular filtration rate (GFR), glomerular collagen deposition, and glomerular basement membrane (GBM) thickening were evaluated. In addition, ROS and collagen IV production by mesangial cells as well as their proliferation was measured in vitro. Diabetic alpha1-null mice developed worse renal disease than diabetic wild-type mice. A significant increase in GFR was evident in the alpha1-null mice at 6 weeks after the STZ injection; it started to decrease by week 24 and reached levels of non-diabetic mice by week 36. In contrast, GFR only increased in wild-type mice at week 12 and its elevation persisted throughout the study. Diabetic mutant mice also showed increased glomerular deposition of collagen IV and GBM thickening compared to diabetic wild-type mice. Primary alpha1-null mesangial cells exposed to high glucose produced more ROS than wild-type cells, which led to decreased proliferation and increased collagen IV synthesis, thus mimicking the in vivo finding. In conclusion, this study suggests that lack of integrin alpha1beta1 exacerbates the glomerular injury in a mouse model of diabetes by modulating GFR, ROS production, cell proliferation, and collagen deposition.

Qi Z, Fujita H, Jin J, Davis LS, Wang Y, Fogo AB, Breyer MD. Characterization of susceptibility of inbred mouse strains to diabetic nephropathy. Diabetes (2005) 54:2628-37
View abstract View in PubMed

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.

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Last updated on 2013-11-06 Moderated by Raymond Harris