Rodent models of diabetic nephropathy: their utility and limitations

Abstract

Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic nephropathy.

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

“…Glomeruli were scored on a semi‐quantitative scale of 0‐3 based on the severity of mesangial matrix expansion . These analyses revealed a modest but statistically significant effect of STZ, consistent with previous reports . However, there was no evidence of a protective effect of TRPC6 inactivation on glomerular pathology, and indeed, there was a trend toward an increase in mesangial matrix expansion simply as a result of TRPC6 inactivation (Figure A,B).…”

Salidroside ameliorates diabetic nephropathy in rats by activating renal AMPK/SIRT1 signaling pathway

“…In contrast, the STZ‐induced rats’ model is widely used to study the early changes in DN and characterized by severe hyperglycemia, hypoinsulinemia, and weight loss, possibly due to the increased catabolic effects of insulin deficiency, volume depletion, and osmotic diuresis (Kitada, Ogura, & Koya, ; Qiao, Gao, Wang, Wang, & Cui, ). In diabetic animal and individuals, the early clinical manifestations of the DN involve increased hyperfiltration, glomerular filtration rate (GFR), and microalbuminuria, whereas the end‐stage of the disease is characterized by severing glomerular damage, proteinuria, macroalbuminuria, oxidative stress, interstitial fibrosis, apoptosis, and impaired kidney function (Ding & Choi, ; Hayashi et al, ; Kitada et al, , ; Mima et al, ; Qiao et al, ; Reidy, Kang, Hostetter, & Susztak, ; Szrejder & Piwkowska, ; Yao, Zhang, & Chen, ).…”

Nano-sized carriers in gene therapy for renal fibrosisin vivo

“…Heat shock protein 47 (HSP47) siRNA with cationized gelatin nanoparticles was shown to knock down HSP47 expression and diminish renal fibrosis in a mouse model of renal fibrosis induced by UUO [53]. Cationic gelatin nanoparticles incorporating plasmid DNA expressing matrix metalloprotease was shown to prevent renal fibrosis in a mouse model of diabetic nephropathy produced by intraperitoneal injection of streptozotocin, which causes damage to the pancreas and results in diabetic nephropathy [54,67]. …”