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We have previously reported the phenotypic features of nephropathy in ZSF rats, a murine model of metabolic syndrome and diabetic nephropathy and commeted that ZSF rats represent the best animal model for human diabetic nephropathy (Prabhakar et al JASN 2007). These studies were conducted exclusively in male ZSF rats while the manifestations both in the phenotype and renal histology in female ZSF rats are largely unknown. These facts together with the recent emphasis on the need to examine both sexes in animal models of experimental research, led us to examine the features of nephropathy in male and female ZSF rats.
To verify our hypothesis, we obtained male and female ZSF rats at 7th week and maintained them in our animal facility with an approved IACUC protocol. Both groups of rats were fed on a special high calorie high fat diet to maintain hyperglycemia. Blood and urine samples were obtained at the start and end of the study and at 48-52 weeks of age all rats were euthanized. Kidneys were harvested and sections were obtained for histopathology and tissue homogenates for RNA isolation as well as protein expression studies.
Our observations show that male ZSF rats had more obesity, hypertension, severe proteinuria and renal failure than the female ZSF rats. Histopathological studies showed that kidneys from male rats demonstrated greater thickening of glomerular basement membrane and greater mesangial hypercellularity and mesangial matrix deposition than female rats (Fig 1 A and B). In addition, male rats had greater arterial thickening and interstitial infiltration than female rats. Furthermore, there was an impressive presence of large proteinaceous casts in the tubules in male rat kidneys compared to female rat kidneys (Fig 2A and B).
In this study, male rats exhibited more severe renal disease than female rats in terms of functional demise as well as structural changes. These findings in our experimental study confirmed our hypothesis that significant differences exist in the phenotypic and histological features of nephropathy despite sharing the same genetic profile and being exposed to same environmental factors, in animal models of metabolic syndrome and diabetes. More studies are warranted to examine the pathogenic factors that contribute to such gender differences in the physical expression of the disease.