Diabetic nephropathy (DN) is a major cause of ESRD worldwide. While many attempts have been made to develop reliable animal models that mimic human disease—ob/ob, db/db obese diabetes type 2 diabetes models, NOD1 mice, streptozotocin (STZ)-induced diabetes model etc., current mouse models still do not display full spectrum of functional and pathological process of human DN (JASN 2009). In addition, it was revealed recently that genetic background has an important effect on the development and severity of diabetic nephropathy. Indeed, C57BL/6 strain, most commonly used for many experimental studies, is highly resistant to diabetic injury.
Recently, Akita mouse gained great interest in research of DN. Let’s start with some history of Akita mouse.
Akita mouse was initially reported as a mouse model mimicking MODY (maturity onset diabetes of the young) in late 1990s (Diabetes 1997). Later, they were found to exhibit type 1 diabetes mellitus via a spontaneous point mutation (C96Y) in the Ins2 gene (Wang JCI 1999), which disrupts a disulphide bond between the insulin A and B chains in a dominant negative way, resulting in misfolding and accumulation of insulin molecules (a.k.a ER stress).
Akita C57BL/6 develops spontaneous hyperglycemia at 400-500 mg/dl range, mild hypertension, and albuminuria approximately 50-100 microgram/ day, at around 3-4 weeks of age. Difference in disease susceptibility, especially in severity of albuminuria, depending on genetic backgrounds was reported. (Gurley, Am J physiol Renal Physiol 2010, Methods Mol Biol 2012)
Here are recent research updates on Akita mice:
KKS (Kallikrein-kinin system)—bradikinin 1/2 receptor deficiency in Akita mouse
ACE inhibitors exhibit renoprotective effects via decrease in intra-glomerular pressure by dilating efferent arterioles. Another explanation of renoprotective effects of ACE inhibitors is via kallikrein-kinin system (KKS). B1R and B2R are the two bradikinin receptors; B2R expresses constitutively and, on the other hand, B1R is inducible by inflammatory stress and DN. Studies by Kakoki et al. (Kakoki PNAS 2004 and PNAS 2010) showed B1R and B2R KO mice developed more severe kidney albuminuria (1.7 x (B2R KO-Akita) and 3.0 x (BR double KO-Akita) compared to Akita WT) and glomerular pathology at 6 or 12 months of age, suggesting potential renoprotective effects of KKS. Hypothesis is that the lack of B2R/B1R enhances oxidative stress via reduction of eNOS and prostaglandins as well as mitochondorial dysfunctions. More details to follow.
eNOS (endothelial Nitric Oxide) deficiency in Akita mice
In humans, three variants in the endothelial NOS (eNOS) gene NOS3—G894T in exon 7, tandem repeats in intron 4, and C786T in the promoter—are associated with DN. Actually, the frequency of G894T is relatively common and 5-9% individuals are homozygous for TT and thus with less activity of eNOS. Wang et al. (Wang et al. PNAS 2011) developed eNOS-/-Akita mouse in B6-129 hybrid background (eNOS-/-Akita in C57BL/6 is lethal around 5 months before developing DN), and showed eNOS KO resulted in increase in glomerular filtration (increase at 3 mo, then decrease at 7 mo), basement membrane thickening, glomerulosclerosis and albuminuria, independent of blood glucose and blood pressure.
Other models in Akita mouse
ACE2 (anigiotensin-conversion enzyme 2) deficiency (Wong et al. Am J physiol 2007) and ketogenic diet (Poplawski et al. PlosONE 2011) in Akita mice have been explored and details to follow.
In summary, Akita mouse is an excellent model of human DN, mimicking both pathophysiology (hyperfiltration and albuminuria) and pathology (GBM thickening and glomerular sclerosis) of kidneys exposed to high serum glucose.