Sex differences in progression of diabetic nephropathy in OVE26 type 1 diabetic mice

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1866; no. 1; p. 165589
• Main Authors: Wang, Wanning, Jiang, Saizhi, Tang, Xiaoqiang, Cai, Lu, Epstein, Paul N., Cheng, Yanli, Sun, Weixia, Xu, Zhonggao, Tan, Yi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2020
• Subjects: Diabetic nephropathy; OVE26 mice; Sexual difference; Type 1 diabetes; Diabetic nephropathy; Sexual difference; Type 1 diabetes; OVE26 mice
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2019.165589

OVE26 mice (FVB background), genetically overexpressing calmodulin in pancreatic beta cells, develop early onset type 1 diabetes, leading to progressive diabetic nephropathy (DN), with features of established human DN. The role of gender in characteristics of renal lesions has remained unexplored. Male and female OVE26 mice were compared to age and sex matched wild-type, nondiabetic FVB mice at ages of 4, 12, 24 and 36 weeks. Nephropathy was examined by measuring urine albumin-to-creatinine ratio, histopathology, expression of pathological markers and immunochemistry in the same cohort of mice. Progression of diabetic kidney disease was evident first in the OVE26 glomerulus, initially as mesangial matrix expansion at 4 weeks followed by loss of podocytes, glomerular volume expansion and severe albuminuria at 12 weeks. Tubule dilation and initiation of interstitial fibrosis did not become significant until 24 weeks. T-lymphocyte infiltration into the renal parenchyma appeared at 36 weeks. OVE26 female mice developed more advanced DN than male OVE26 mice, such as more severe albuminuria, greater podocyte loss, additional fibrosis and significantly more inflammatory cell infiltration. The female OVE26 mice had lowest level of plasma estradiol in all 36 weeks old mice, as well as renal estrogen receptors. This demonstration of the role of gender, combined with the detailed characterization of DN progression illustrates the value of OVE26 mice for understanding gender effects on DN and provides the basis for researchers to better select the age and sex of OVE26 mice in future studies of type 1 DN. What is already known about this subject?•OVE26 mice, genetically overexpressing calmodulin in pancreatic beta cells, develop early onset type 1 diabetes.•OVE26 mice are a widely used and valuable rodent model which develop severe, progressive diabetic nephropathy, with features of established human diabetic nephropathy. What is the key question?•Does gender play a role in determining characteristics of renal lesions and severity of nephropathy? What are the new findings?•Female OVE26 mice had more severe albuminuria, greater podocyte loss.•Female OVE26 mice had additional fibrosis and significantly more inflammatory cell infiltration.•Diabetes induced reductions in estradiol levels and renal estrogen receptors may be responsible for the female sensitization to DN in OVE26 mice. How might this impact on clinical practice in the foreseeable future?•Our findings provide the basis for researchers to better select the age and sex of OVE26 mice in future studies of type 1 DN.