Sex Differences in the Progression of Type 2 Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause of chronic renal disease. To explore the age‐related progression and sexual dimorphisms in the development of DN, we used a rat model of type 2 diabetic nephropathy (T2DN). The T2DN rat was previously created by introgression of the mitochondria and some passenger loci from the Fawn Hooded Hypertensive rat into the background of the Goto‐Kakizaki (GK; type 2 diabetic) rat. Type 2 diabetes in T2DN rats is accompanied by renal histologic abnormalities that are characteristic of DN, similar to clinical observations in human patients. The experimental groups were Wistar (non‐diabetic controls), GK, or T2DN rats at the early stages of DN (12 weeks old) or the late stages of the disease (>40 weeks of age). At the early stage of DN, male T2DN and GK rats showed significant increases in blood glucose (374 ± 96 and 329 ± 45 vs. 280 ± 24 mg/dL in Wistar, respectively) and kidneys to body weight ratio (10.05 ± 1.19 and 9.39 ± 0.78 vs. 7.31 ± 1.13 mg/g, respectively). In the late stage of the disease progression, T2DN rats had a significant increase in renal damage compared with GK and Wistar rats, indicated by progressive albuminuria, diuresis, a high prevalence of medullary protein cats, and glomerular lesions. Besides a striking DN phenotype in the T2DN model, we found significant sex differences in the development and progression of the disease. The male weight was double that of females (414 ± 27 vs. 264 ± 19 g, respectively), which correlates with a significant difference in postprandial blood glucose levels (435 ± 50 vs. 353 ± 46 mg/dL, respectively). To further evaluate changes in type 2 diabetes between the sexes, we performed the glucose tolerance test (GTT) in fasting animals. The male GTT indicates significant impairment in the body's response to sugar load compared to the female (155 ± 18 vs. 118 ± 5 at control and 378 ± 19 vs. 183 ± 48 mg/dL after oral glucose gavage; male vs female respectively). Blood tests also show elevated levels of serum alkaline phosphatase (158 ± 32 U/L) and cholesterol in males, similar to the clinical observations in patients with diabetes mellitus. Analysis of the renal damage between the sexes reveals significant increases in protein cast formation and glomerular abnormalities indicated by a high percentage of damaged glomeruli in males (28% vs. 4% in females). Aged male T2DN rats also had increases in nephrin shedding in their urine, which correlates with the dramatic differences in albuminuria. In T2DN males, there was an inverse correlation in serum levels (2.5 ± 0.2 vs. 3.3 ± 0.1 g/dL) and urinary excretion of albumin (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio) in comparison to females of similar age. Here we report that T2DN rat develops renal and physiological lesions to those seen in patients with type 2 diabetes, and there is a dramatic sex difference in the progression of renal damage.Support or Funding InformationNHLBI R35 HL135749 and P01 HL116264AHA 17SDG33660149 and 18PRE34030127ADA 1‐15‐BS‐172This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.