The Nrf2/HO-1 Pathway Mediates the Antagonist Effect of L-Arginine On Renal Ischemia/Reperfusion Injury in Rats

Abstract

Background/Aims: Ischemia/reperfusion (I/R) is the most common cause of acute renal injury. I/R-induced oxidative stress is involved in the development of acute renal injury, which can be reversed by supplementation with L-arginine, a precursor of nitric oxide (NO). This study was conducted to evaluate alterations in the expression of transcription factors [nuclear factor kappa B (NF-κB), nuclear factor-E2-related factor-2 (Nrf2), and heme oxygenase 1 (HO-1)] and heat shock protein 70 (HSP70) in the kidney of I/R-induced injury rats. Methods: Sprague-Dawley (SD) rats were subjected to bilateral renal ischemia for 45 min followed by reperfusion for 24 h. Group 1, Sham; group 2, I/R; group 3, L-arginine; and group 4, L-arginine+zinc protoporphyrin (ZnPP). The levels of serum creatinine (Scr), blood urea nitrogen (BUN), serum nitric oxide (NO), histic malondialdehyde (MDA) and reactive oxygen species (ROS) and superoxide dismutase (SOD) activity were determined, and the expression levels of Nrf2, HO-1, NF-κB, and HSP70 were evaluated. Results: The treatment of rats with L-arginine produced a significant reduction in the levels of BUN, Scr, MDA and a significant enhancement in the level of NO and in the activity of SOD compared to renal I/R groups. The expression levels of Nrf2, HO-1, and HSP70 were strongly increased, and the expression of NF-κB and production of ROS were significantly decreased in the L-arginine group compared to that of the I/R group. ZnPP increased renal damage and displayed effects opposite to those of L-arginine. Conclusion: These findings suggested that L-arginine/NO reduces renal dysfunction associated with I/R of the kidney and may act as a trigger to regulate the NF-κB, HSP70 and Nrf2/HO-1 signaling cascades.

Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease

“…Several strategies to induce HO-1 apart from the traditional porphyrin-based compounds and heme have been reported. These include targeting of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 and Nrf2, respectively) [121,122,123], and treatment with resveratrol and electroacupuncture [124,125]. One area in which research into the protective actions of HO induction is lacking is in large animal models of cardiovascular and renal disease.…”

Crocetin alleviates myocardial ischemia/reperfusion injury by regulating inflammation and the unfolded protein response

“…classical mechanical hypotheses suggest that cro protected against I/R injury in the brain and heart via an antioxidant response. However, previous studies demonstrated that inflammation served an important role in reperfusion injury, causing a secondary cascade of lethal damage (2,12). Therefore, it was suggested that CRO had the ability to reduce the inflammatory response induced by reperfusion injury.…”

“…In Nrf2-deficient mice, the cardiovascular phenotype is more impaired, even in the ischemic preconditioning model, due to its important function in the cardiovascular system (9). Previous studies demonstrated that Nrf2/heme oxygenase-1 (HO-1) signaling plays an important role in I/R injury in different organs (10)(11)(12)(13). Activation of Nrf2/HO-1 signaling is an effective method to attenuate myocardial I/R injury in several previous pharmacological studies (14,15).…”

Regulatory Mechanisms of Baicalin in Cardiovascular Diseases: A Review

“…In addition, Nrf2, a redox-sensitive transcription factor, is crucial to inhibit oxidative stress in cells (Gallorini et al, 2015). Once activated, Nrf2 can transactivate genes driven by antioxidant response elements (ARE), especially HO-1 (Tong and Zhou, 2017). Herein, it has been reported that the Nrf2/HO-1 pathway exhibits protective roles in ischemic disorders, including MI (Zeng et al, 2015).…”