Samed Emre DARILMAZ, İlknur BİNGÜL, Merva SOLUK TEKKEŞİN, Nergis DEMİR, Seldağ BEKPINAR

Cyclosporine Treatment Increases The ACE/ACE2 Ratio in Adipose Tissue and Aorta

Objective: The renin-angiotensin system (RAS) mainly functions in the regulation of vascular tone. Since the perfusion and storage capacity of adipose tissue is largely dependent on vessel density and tone, factors that modulate vasoactive RAS components may affect adipose tissue metabolism. Cyclosporine, an immunosuppressive drug, has some detrimental effects on the vascular system and kidneys by modulating the components of the RAS. However, the effect of cyclosporine on adipose tissue is still not clear. In this study, the impact of cyclosporine on mRNA expressions of some "RAS components" in the aorta and epididymal adipose tissue of rats were investigated. Materials and Methods: Rats were injected subcutaneously with cyclosporine at a dose of 25 milligrams per kilogram per day for 1 week. Angiotensin II, angiotensin (1-7), blood urea nitrogen and creatinine levels were examined in serum samples of rats. mRNA expressions of RAS components in the aorta and epididymal adipose tissue, and hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) in epididymal adipose tissue were determined. In addition, histopathological examinations of the adipose tissue were performed. Results: Cyclosporine administration significantly suppressed the expression of angiotensin-converting enzyme 2 (ACE2) in both the aorta and adipose tissue. Accordingly, it caused a significant increase in the ACE/ACE2 ratio. However, it did not affect the adipose tissue HIF-1 and VEGF expressions. When examined histopathologically, no change was observed in the vascular density of adipose tissue due to cyclosporine. Conclusion: It was thought that the increase in the ACE/ACE2 ratio might be an adaptation that protects the adipose tissue against the systemic effect of cyclosporine.

Keywords:

Cyclosporine, adipose tissue, angiotensin-converting enzyme 2, vascular density,

PDF

___

1. Hokova L, Malek I, Kopkan L, Kautzner J. Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension. Physiol Res 2017; 66: 167-80. google scholar
2. Cassis LA, Police SB, Yiannikouris F, Thatcher SE. Local adipose tissue renin-angiotensin system. Curr Hypertens Rep 2008; 10: 93-8. google scholar
3. Slamkova M, Zorad S, Krskova K. Alternative renin-angiotensin system pathways in adipose tissue and their role in the pathogenesis of obesity. Endocr Regul 2016; 50: 229-40. google scholar
4. Fuhrmann A, Lopes P , Sereno J , Pedro J, Espinoza DO , Pereira MJ, et al. Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model. Biochem Pharmacol 2014; 88: 216- 28. google scholar
5. Damiano S, Trepiccione F, Ciarcia R, Scanni R, Spagnuolo M, Maco l, et al. A new recombinant MnSOD prevents the cyclosporine A-induced renal impairment. Nephrol Dial Transplant 2013; 28(8): 2066-72. google scholar
6. Porter G A, Bennett WM, Sheps SG. Cyclosporine-associated hypertension. National High Blood Pressure Education Program. Arch Intern Med 1990; 150(2): 280-3. google scholar
7. Marienhagen K, Lehner F , Klempnauer J , Hecker H, Borlak J. Treatment of cyclosporine induced hypertension: Results from a long-term observational study using different antihypertensive medications. Vascul Pharmacol 2019; 115: 69-83. google scholar
8. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond) 2009; 33: 54-66. google scholar
9. Jackson WF. Myogenic tone in peripheral resistance arteries and arterioles: The pressure is on! Front Physiol 2021; 12: 699517. google scholar
10. Roman RJ, Van Dokkum RP. Commentary on the special issue on the impact of myogenic tone in health and disease. Curr Vasc Pharmacol 2014; 12: 779. google scholar
11. Gonzales AL, Yang Y, Sullivan MN, Sanders L, Dabertrand F, Hill-Eubanks DC, et al. A PLCgamma1-dependent, force-sensitive signaling network in the myogenic constriction of cerebral arteries. Sci Signal 2014; 7: ra49. google scholar