Upregulation of antioxidant nuclear factor erythroid 2-related factor 2 and its dependent genes associated with enhancing renal ischemic preconditioning renoprotection using levosimendan and cilostazol in an ischemia/reperfusion rat model

Mona K Tawfik; Samy Makary; Mohammed M Keshawy

doi:10.5114/aoms/111373

Upregulation of antioxidant nuclear factor erythroid 2-related factor 2 and its dependent genes associated with enhancing renal ischemic preconditioning renoprotection using levosimendan and cilostazol in an ischemia/reperfusion rat model

Arch Med Sci. 2021 Jan 28;17(6):1783-1796. doi: 10.5114/aoms/111373. eCollection 2021.

Authors

Mona K Tawfik¹, Samy Makary², Mohammed M Keshawy³

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
² Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
³ Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.

Abstract

Introduction: Ischemic preconditioning (Ipre) provides protection against renal ischemia-reperfusion (I/R) injury with its associated remote organ damage. This study examined the enhancing protective effect of Ipre with levosimendan or cilostazol in I/R-induced kidney and lung injury in a rat model.

Material and methods: Rats were divided into: sham-operated, I/R control, Ipre control, I/R + cilostazol or levosimendan and Ipre + cilostazol or levosimendan. Drugs were given 30 min before left renal I/R or 4 cycles of Ipre just before renal ischemia.

Results: The Ipre combined with the implemented drugs enhanced physiological antioxidant defense genes including renal nuclear factor erythroid 2-related factor 2 (Nrf2) and its dependent genes heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1) and improved malondialdehyde and superoxide dismutase renal tissue levels. The combined effect improved I/R consequences for blood urea, creatinine, and creatinine clearance and improved blood oxygenation and metabolic acidosis. Moreover, the combination improved the renal soluble intercellular adhesion molecule (ICAM), tumor necrosis factor α (TNF-α) and interlukin-6 (IL-6) with histopathological improvement of tubular necrosis with a decrease in the apoptotic marker caspase-3 and an increase in the anti-apoptotic Bcl-2 expression.

Conclusions: Cilostazol or levosimendan potentiates the renoprotective effect of Ipre against renal I/R injury, associated with upregulation of antioxidant genes Nrf2, HO-1, and NOQ-1 expression.

Keywords: cilostazol; ischemic preconditioning; levosimendan; nuclear factor-erythroid-2-related factor 2; renal ischemia reperfusion.