Recent Advances in Animal Models of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the single most common cause of end-stage kidney disease. Therefore, it is imperative that novel therapies are developed. Progress has been hindered, however, by the lack of robust animal models. In the current review we describe recent advances in the field, including the impact of background strain, hypertension and transcriptomic profiling. While the C57BL/6J strain is relatively resistant to DN, the FVB strain appears more susceptible and Ove26 and db/db mice on this background may be useful in modelling types 1 and 2 DN, respectively. Black and tan, brachyury (BTBR) mice deficient for the leptin receptor (ob/ob) develop many of the pathological features of human DN and, remarkably, treatment with exogenous leptin ameliorates hyperglycaemia, albuminuria and glomerulosclerosis. Hypertension plays a key role in the progression of human DN and exacerbates nephropathy in diabetic rodents. Endothelial nitric oxide synthase deficiency (eNOS^-/-) results in moderate hypertension and the development of nodular glomerulosclerosis and hyaline arteriosclerosis in streptozotocin-induced diabetic C57BL/6J mice. In Cyp1a1mRen2 rats, renin-dependent hypertension synergises with streptozotocin-induced hyperglycaemia to produce a 500-fold increase in albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. Renal transcriptional profiling suggests that many of the gene expression changes observed in human DN are replicated in eNOS^-/- mice and Cyp1a1mRen2 rats. Despite these advances, no model faithfully recapitulates all the features of human DN and further refinements are required. In the interim, it is likely that researchers may use publically available transcriptomic data to select the most appropriate model to study their molecule or pathway of interest.

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

“…2013; Betz and Conway 2014). A single dose of STZ is not toxic to the kidney or to the proximal tubule, as shown previously by Palm et al.…”

Longitudinal Changes in Measured Glomerular Filtration Rate, Renal Fibrosis and Biomarkers in a Rat Model of Type 2 Diabetic Nephropathy

“…Most mouse models do not develop this pathology [6,7,8]. In 1K-obese ZSF-1 rats, fibrosis rose to 9.8% of the interstitial space by 12 weeks after the nephrectomy, which was significantly higher than the male lean ZSF-1 controls at that time point, and by week 24, it had progressed to 18.8% of the area.…”

“…However, a suitable preclinical animal model that mimics human DN has been lacking. Most animal models, particularly mouse models, do not manifest TI fibrosis and do not develop a progressive decline in renal function, although most show proteinuria/albuminuria and glomerular pathology [5,6,7,8,9]. The diabetic obese ZSF-1 rat is a relatively new animal model of type II DN that displays many clinical features of human disease [5,10,11].…”

Antagonism of vasopressin V2 receptor improves albuminuria at the early stage of diabetic nephropathy in a mouse model of type 2 diabetes

“…It allows for the study of the early stage of diabetic nephropathy but like other genetic or dietary models of type 2 diabetes, it does not reproduce features of evolved human diabetic kidney disease (Betz et al, 2014). Also, we chose to limit the experiment to 12 weeks in order to avoid hydronephrosis or dehydration related to high urine output caused by diabetes and V2R treatment.…”