Naringenin Alleviates Renal Ischemia Reperfusion Injury by Suppressing ER Stress-Induced Pyroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling Pathway

Abstract

Endoplasmic reticulum (ER) stress, pyroptosis, and apoptosis are critical molecular events in the occurrence and progress of renal ischemia reperfusion (I/R) injury. Naringenin (4 ′ ,5,7-trihydroxyflavanone) is one of the most widely consumed flavonoids with powerful antioxidant and anti-inflammatory activities. However, whether naringenin is able to relieve renal I/R injury and corresponding mechanisms have not been fully clarified. This study was aimed at exploring its role and relevant mechanisms in renal I/R injury. The C57Bl/6 mice were randomly assigned to receive administration with naringenin (50 mg/kg/d) or sterile saline (1.0 mL/d) for 3 d by gavage and suffered from renal I/R surgery. One specific ER stress inhibitor, 4-phenylbutyric acid (4-PBA, 100 mg/kg/d), was intraperitoneally administered to validate the regulation of ER stress on pyroptosis and apoptosis. Cultured HK-2 cells went through the process of hypoxia/reoxygenation (H/R) to perform cellular experiments with the incubation of naringenin (200 μM), 4-PBA (5 mM), or brusatol (400 nM). The animal results verified that naringenin obviously relieved renal I/R injury, while it refined renal function and attenuated tissue structural damage. Furthermore, naringenin treatment inhibited I/R-induced ER stress as well as pyroptosis and apoptosis as indicated by decreased levels of specific biomarkers such as GRP78, CHOP, caspase-12, NLRP3, ASC, caspase-11, caspase-4, caspase-1, IL-1β, GSDMD-N, BAX, and cleaved caspase-3 in animals and HK-2 cells. Besides, the upregulated expression of Nrf2 and HO-1 proteins after naringenin treatment suggested that naringenin activated the Nrf2/HO-1 signaling pathway, which was again authenticated by the usage of brusatol (Bru), one unique inhibitor of the Nrf2 pathway. Importantly, the application of 4-PBA showed that renal I/R-generated pyroptosis and apoptosis were able to be regulated by ER stress in vivo and in vitro. In conclusion, naringenin suppressed ER stress by activating Nrf2/HO-1 signaling pathway and further alleviated pyroptosis and apoptosis to protect renal against I/R injury.

Nephroprotective Effects of Cardamonin on Renal Ischemia Reperfusion Injury/UUO-Induced Renal Fibrosis

“…28,40 Excessive and permanent OS inevitably triggered renal cell death by intensifying endoplasmic reticulum stress, pyroptosis, and apoptosis as testified by our published studies. 9,21,24,41 However, the regulatory mechanisms of oxidative stress in AKI or CKD are not absolutely identical despite the crucial participation of OS. 28,38−40 In recent years, relevant studies frequently demonstrated that suppressing OS would be capable of ameliorating renal fibrosis or AKI to a large extent.…”

“…Destructive or persistent pathological circumstances stimulated the unrestrained formation of ROS, leading to harmful disturbance on antioxidative defense and distinguished repression of antioxidant enzymes (SOD, CAT, etc. ). , Excessive and permanent OS inevitably triggered renal cell death by intensifying endoplasmic reticulum stress, pyroptosis, and apoptosis as testified by our published studies. ,,, However, the regulatory mechanisms of oxidative stress in AKI or CKD are not absolutely identical despite the crucial participation of OS. ,− In recent years, relevant studies frequently demonstrated that suppressing OS would be capable of ameliorating renal fibrosis or AKI to a large extent. − Therefore, identifying and targeting the common pathways or molecules seem to be promising and necessary for treating kidney diseases. , Hopefully, some of the antioxidants and anti-inflammation regents have already been tested in clinical trials in patients with relevant kidney diseases and have exhibited encouraging end results. For example, Pablo E Pergola and his colleagues discovered that the oral administration of bardoxolone methyl, one modulator of antioxidant and anti-inflammation, upgraded the estimated glomerular filtration rate in patients along with type 2 diabetes and CKD at 24 weeks .…”

“…The routinely completed process in protein detection was as presented previously . Briefly, the protein content quantification was performed by the utilization of Enhanced Bicinchoninic Acid (BCA) Protein Assay Kit (P0010, Beyotime, Shanghai) according to product instructions once the protein was extracted.…”

Apelin-13 alleviates contrast-induced acute kidney injury by inhibiting endoplasmic reticulum stress

“…Activation of the Nrf2 pathway has been shown to reduce the accumulation of misfolded proteins that can contribute to ER stress. In addition, activation of the Nrf2 pathway may also help to reduce inflammation and cell death that can result from ER stress [ 38 , 39 ]. Interestingly, as a regulatory transcription factor, Nrf2 has also been reported to be a direct substrate of PERK [ 40 ].…”

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Flavonoids, as one of the most common plant secondary metabolites, have various biological properties such as free radical scavenging, antioxidation, antibacterial, and anti-inflammatory activities. − Interestingly, numerous preclinical studies have demonstrated that flavonoids can regulate different forms of regulated cell death (RCD), including pyroptosis, apoptosis, necroptosis, and ferroptosis, thereby preventing disease progression. − Of these, ferroptosis, first coined in 2012, is a newly identified iron-dependent form of RCD characterized by a catastrophic accumulation of lipid peroxides . Ferroptosis has aroused great interest in the scientific community due to its morphological features and regulatory mechanisms that are different from other RCD .…”