Sex Hormones and Development of Advanced Diabetic Nephropathy in Diabetic Kidney Disease
Authors: Spires Denisha R. , Levchenko Vladislav , Kriegel Alison , Isaeva Elena , Klemens Christine A. , Khedr Sherif , Cheng Xi , Yeo Ji-Youn , Joe Bina , Staruschenko Alexander , Palygin Oleg 
Published: April 2020

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end‐stage renal failure and increases the risk of cardiovascular disease. Hyperglycemia promotes the development of renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity‐ and age‐related risk factors. Recently, we described the development of advanced forms of diabetic nephropathy (DN) and glomerular damage in the type 2 diabetic nephropathy (T2DN) rat model. Since the progression of renal disease in T2DN rats closely parallels that of human DKD, we questioned whether this strain also displays sexual dimorphisms comparable to the human population. Male and female T2DN rats at >48 weeks of age were used to evaluate hyperglycemia, renal injury, and renal function during the advanced stage of DN. We found that there were significant differences in fasting blood glucose levels for males versus females (156 ± 8 vs. 124 ± 4 mg/dL, respectively). Glucose tolerance tests revealed a higher prevalence of glucose intolerance in males (378 ± 19 vs. 183 ± 48 mg/dL for male vs. female). The development of albuminuria and glomerular damage was significantly different between sexes (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio, and 28 vs. 4 % with the highest damage score, male vs. female). These changes, accompanied by a significant increase in urinary nephrin shedding in males, suggested pathological changes to the glomerular filtration barrier. Detailed analyses of plasma samples also indicated striking differences in cholesterol (261.2 ± 46.7 vs. 86.7 ± 2.7 mg/dL), blood urea nitrogen (22.2 ± 2 vs. 17.1 ± 0.8 mg/dL), albumin homeostasis and alkaline phosphatase (ALP) levels in males compared to females. Echocardiography analyses of the cardiac output, left ventricle wall thickness, fractional shortening, and heart rate did not differ between strains, suggesting that the DN‐related effects on renal and metabolic phenotypes in the T2DN rats do not induce additional cardiac pathology. Additionally, microbiome analyses indicate that the contribution of microbiota to the observed gender differences in T2DN phenotypes is minimal. To test the role of the endocrine environment in physiology and pathophysiology of type 2 diabetes, we performed gonadectomy on male and female T2DN rats at 9 to 10 weeks old. We found that at 32 weeks of age, gonadectomized male T2DN rats have a significant reduction in fasting blood glucose versus their intact controls; however, female rats have no significant changes between groups (128 ± 9 vs. 170 ± 14, and 94 ± 4 vs. 105 ± 4 mg/dL for gonadectomized vs. control male and female rats, respectively). In conclusion, sex differences in the T2DN renal phenotype are ultimately the result of multiple changes and potentially depend on male hormonal signaling, which likely stimulates the progression of diabetes and the development of renal damage.

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NIH HL135749, AHA 18PRE34030127 , VA I01 BX004024