An Overview of Sex-Based Differences in the Onset and Progression of DKD in the Well-Known Model, ZSF1 Rats

A better understanding of diabetic kidney disease (DKD) will help optimize its management. Few animal models replicate human DKD characteristics as closely as ZSF1 male rats. To address the male-specific focus in murine model systems, we aimed to characterize the manifestation of DKD in ZSF1 females and compare them with ZSF1 males and control rats (CD). ZSF1 males become obese at an early age. ZSF1 females are fatter and heavier than CD females but remain smaller, lighter, and more active than ZSF1 males throughout their lives. Male, but not female, ZSF1 rats become hypertensive with age. ZSF1 females have a higher heart rate in early life, which reduces significantly with age. ZSF1 males exhibit significant hyperglycemia from an early age. In contrast, female ZSF1 are not overly hyperglycemic; however, their blood glucose levels trend higher than those of CD females, and the difference is statistically significant. Both ZSF1 males and females develop progressive proteinuria. ZSF1 females, therefore, display various features of DKD: higher-trending blood glucose levels, hyperlipidemia, and progressive proteinuria, but not hypertension. Thus, ZSF1 female rats may be a suitable model for studying DKD without hypertension and for testing the effects of DKD-relevant drug responses in females.