Initial Characterization of a Rat Model of Diabetic Nephropathy

Abstract

The lack of an appropriate animal model that spontaneously develops diabetic nephropathy has been a significant limitation in the search for genetic factors underlying this disease and the development of new therapeutic strategies to prevent progressive renal disease in diabetes. We introgressed the mitochondria and some passenger loci from the FHH/EurMcwi rat into the genetic background of diabetic GK rats, creating a new rat strain, T2DN (T2DN/Mcwi). Despite the high degree of genetic similarity between T2DN and GK rats (97% at 681 loci), diabetes ensues earlier and progresses more severely in T2DN rats. T2DN rats exhibit proteinuria by 6 months of age, accompanied by renal histologic abnormalities such as focal glomerulosclerosis, mesangial matrix expansion, and thickening of basement membranes. These characteristics progress over time, and nearly all T2DN rats exhibit diffuse global glomerulosclerosis with nodule formation and arteriolar hyalinosis by 18 months of age. The histologic changes in the kidney of T2DN rats closely mimic the changes seen in the kidney of patients with diabetes. These results indicate that the T2DN rat is a suitable model for investigating diabetic nephropathy. Here we report the initial genetic and physiological characterization of this new rat model of diabetic nephropathy. Diabetes 53: [735][736][737][738][739][740][741][742] 2004 O ne of the major morbidity and mortality factors confronted by patients with diabetes is an increased risk of developing diabetic nephropathy that often progresses to end-stage renal disease (ESRD) (1-3). A long-standing question pertaining to the development of renal disease in diabetes concerns the mechanisms involved in this process. A wealth of data have been generated on possible mechanisms by which diabetes and its ancillary metabolic, hemodynamic, growth, and glomerular cell injury-related alterations may modulate the progression of diabetic nephropathy (4 -7). Nevertheless, the observation that approximately two-thirds of patients with diabetes do not develop renal disease indicates that hyperglycemia is a permissive factor in diabetic nephropathy, but elevated plasma glucose levels alone do not fully account for renal injury (1). Thus, genetic factors are thought to play an important role in the susceptibility for diabetic nephropathy, with several clinical and epidemiologic studies supporting this hypothesis (8 -10).The complex interplay between diabetes-dependent and -independent factors in determining the progression of renal disease could become more amenable to study if there were adequate animal models that spontaneously develop diabetes and renal lesions that mimic those seen in patients with diabetic nephropathy. However, to date, no rodent model of diabetes that fully recapitulates the chronology of events and histologic changes in the kidney that are characteristic of patients with diabetic nephropathy has been developed. Several rodent models of spontaneous diabetes, such as the Zucker rat, BB rat, and DB mice, exhibit glomerula...

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

“…This new T2DM rat model was named T2DN, which is a non-obese rat model that develops diabetes spontaneously as GK rats but with proteinuria and abnormal renal histological findings (4). Genetic analysis indicated that the two major differences between GK and T2DN are passenger loci (3%) and mtDNA (4). Specific sequence analysis of mtDNA showed that the T2DN rats carry mitochondria from FHH, whereas the GK carries mitochondria from Wistar Kyoto (WKY/NCrl) rats (5).…”

“…This new T2DM rat model was named T2DN, which is a non-obese rat model that develops diabetes spontaneously as GK rats but with proteinuria and abnormal renal histological findings (4). Genetic analysis indicated that the two major differences between GK and T2DN are passenger loci (3%) and mtDNA (4).…”

“…A new rat model of type 2 diabetes mellitus was developed by crossing diabetic male Goto-Kakizaki (GK) rats with female Fawn Hooded Hypertensive (FHH) rats (4). This new T2DM rat model was named T2DN, which is a non-obese rat model that develops diabetes spontaneously as GK rats but with proteinuria and abnormal renal histological findings (4).…”

“…Measurement of plasma glucose, serum cholesterol, and triglyceride concentrations were performed by Marshfield Laboratories (Marshfhield, WI) as described previously (8). Plasma glucose levels were measured by standard procedures as described (4). Glycosylated hemoglobin (HbA 1c ) was measured using in2itTM (Bio-Rad) according to the manufacturer's protocol.…”

Diabetic Nephropathy in Spontaneously Diabetic Torii (SDT) Rats

“…Goto-Kakizaki (GK) rats, a nonobese type2 diabetes model, exhibited proteinuria by 6 months of age, accompanied by renal histologic abnormalities such as focal glomerulosclerosis, mesangial matrix expansion, and thickening of basement membranes. Furthermore, diffuse global glomerulosclerosis with nodule formation and arteriolar hyalinosis were exhibited by 18 months of age [8,9]. In Zucker Diabetic Fatty (ZDF) rats, an obese type 2 diabetes model, proteinuria started to rise until 3 months of age.…”