Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8

Ines Marek, Maurizio Canu, Nada Cordasic, Manfred Rauh, Gudrun Volkert, Fabian B. Fahlbusch, Wolfgang Rascher, Karl F. Hilgers, Andrea Hartner, Carlos Menendez-Castro

Apoe-deficient (Apoe(-/-)) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe(-/-) mice deficient in the mesenchymal integrin chain Itga8 (Itga8(-/-)). Here, we used this Apoe(-/-), Itga8(-/-) mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model. Apoe(-/-) mice were backcrossed with Itga8(-/-) mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe(-/-)Itga8(+/+) mice or Apoe(-/-)Itga8(-/-) mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed. When compared to male mice, Apoe(-/-)Itga8(+/+) female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe(-/-) mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different. In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.