Rodent animal models: from mild to advanced stages of diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is a secondary complication of both type 1 and type 2 diabetes, resulting from uncontrolled high blood sugar. 30-40% of diabetic patients develop DN associated with a poor life expectancy and end-stage renal disease, causing serious socioeconomic problems. Although an exact pathogenesis of DN is still unknown, several factors such as hyperglycemia, hyperlipidemia, hypertension and proteinuria may contribute to the progression of renal damage in diabetic nephropathy. DN is confirmed by measuring blood urea nitrogen, serum creatinine, creatinine clearance and proteinuria. Clinical studies show that intensive control of hyperglycemia and blood pressure could successfully reduce proteinuria, which is the main sign of glomerular lesions in DN, and improve the renal prognosis in patients with DN. Diabetic rodent models have traditionally been used for doing research on pathogenesis and developing novel therapeutic strategies, but have limitations for translational research. Diabetes in animal models such as rodents are induced either spontaneously or by using chemical, surgical, genetic, or other techniques and depicts many clinical features or related phenotypes of the disease. This review discusses the merits and demerits of the models, which are used for many reasons in the research of diabetes and diabetic complications.

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].…”

Association of angiotensin-converting enzyme insertion/deletion polymorphism with type 1 diabetic nephropathy: a meta-analysis

“…As a leading cause of end-stage renal disease, DN is accompanied by serious socioeconomic problems. 1 Various polymorphisms of genes, especially angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms, have been reported associated with DN. The ACE I/D gene polymorphism is characterized by the presence or absence of a 278 bp Alu repetitive sequence in intron 16.…”

Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner

“…A number of animal models have been developed to provide valuable information for studying the pathogenesis, progression, involved signaling pathways, and potential therapeutic approaches of DN (Betz and Conway, 2014, 2016; Breyer et al, 2005; Kaur et al, 2014; Soler et al, 2012). However, most of the current animal models can only recapitulate the early stages of DN (Soler et al, 2012), and lack severe human-like histopathological features of advanced DN, such as nodules in the glomerular tuft and glomerulosclerosis (Breyer et al, 2005; Fujita et al, 2012; Soler et al, 2012), which has largely delayed the progress of research on DN.…”

“…The MDMX gene modification of this mouse line specifically occurs in pancreatic endocrine cells, so the resulting diabetes and subsequent advanced DN essentially initiate from the dysfunction of β-cells, which is similar to human type 1 diabetes, and excludes some artificial and unidentified influence from other organs, such as the non-natural changes in kidney eNOS-knockout mouse line may have due to the systemic eNOS deficiency (Takahashi and Harris, 2014), the direct and non-specific kidney toxicity STZ may cause (Betz and Conway, 2016; Breyer et al, 2005), and atypical features of DN as found in NONcNZO10/LtJ strain (Soler et al, 2012). Furthermore, unlike other models, such as STZ-treated mice that easily die from hypoglycemia or ketoacidosis (Kaur et al, 2014), this is a relatively stable, simple, and economical mouse line to be handled, requiring no special treatment. The reason why the blood glucose level of the MDMX-knockout mouse line was stably kept at 300–600 mg/dl (Fig.…”