An Update on the Use of Animal Models in Diabetic Nephropathy Research

Abstract

In the current review, we discuss limitations and recent advances in animal models of diabetic nephropathy (DN). As in human disease, genetic factors may determine disease severity with the murine FVB and DBA/2J strains being more susceptible to DN than C57BL/6J mice. On the black and tan, brachyuric (BTBR) background, leptin deficient (ob/ob) mice develop many of the pathological features of human DN. Hypertension synergises with hyperglycemia to promote nephropathy in rodents. Moderately hypertensive endothelial nitric oxide synthase (eNOS−/−) deficient diabetic mice develop hyaline arteriosclerosis and nodular glomerulosclerosis and induction of renin-dependent hypertension in diabetic Cyp1a1mRen2 rats mimics moderately severe human DN. In addition, diabetic eNOS−/− mice and Cyp1a1mRen2 rats recapitulate many of the molecular pathways activated in the human diabetic kidney. However, no model exhibits all the features of human DN; therefore, researchers should consider biochemical, pathological, and transcriptomic data in selecting the most appropriate model to study their molecules and pathways of interest.

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

“…Researchers have tried to replicate the hemodynamic effects of diabetes and hypertension in rodent models by administering high protein diets or by uninephrectomy, which both elevate glomerular hydrostatic pressure, or by superimposing diabetes on genetic models of hypertension 15 . For example, in transgenic rodents with excessively activated RAAS to induce hypertension there is accelerated development of diabetic nephropathy.…”

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.…”

“…We believe that the MDMX-conditional knockout mouse line may serve as a reliable and promising new model for studying advanced DN and developing new therapeutic strategies. 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.…”

Mechanisms of metabolic memory and renal hypoxia as a therapeutic target in diabetic kidney disease

“…Recent large clinical trials on DKD included patients with kidney diseases other than the classical DN; the inclusion criteria in these trials did not require proof of DN by renal biopsy, absence of hematuria, duration of diabetes mellitus or existence of diabetic retinopathy in type 2 diabetes mellitus patients [9][10][11][12][13] . Diabetic animal models have been utilized, but these have rarely shown the classic pathological changes in DN [14][15][16][17][18] . These differences must be taken into consideration when comparing clinical studies and animal experiments.…”