Gastrin Attenuates Renal Ischemia/Reperfusion Injury by a PI3K/Akt/Bad-Mediated Anti-apoptosis Signaling

Abstract

Ischemic/reperfusion (I/R) injury is the primary cause of acute kidney injury (AKI). Gastrin, a gastrointestinal hormone, is involved in the regulation of kidney function of sodium excretion. However, whether gastrin has an effect on kidney I/R injury is unknown. Here we show that cholecystokinin B receptor (CCKBR), the gastrin receptor, was significantly up-regulated in I/R-injured mouse kidneys. While pre-administration of gastrin ameliorated I/R-induced renal pathological damage, as reflected by the levels of serum creatinine and blood urea nitrogen, hematoxylin and eosin staining and periodic acid-Schiff staining. The protective effect could be ascribed to the reduced apoptosis for gastrin reduced tubular cell apoptosis both in vivo and in vitro. In vitro studies also showed gastrin preserved the viability of hypoxia/ reoxygenation (H/R)-treated human kidney 2 (HK-2) cells and reduced the lactate dehydrogenase release, which were blocked by CI-988, a specific CCKBR antagonist. Mechanistically, the PI3K/Akt/Bad pathway participates in the pathological process, because gastrin treatment increased phosphorylation of PI3K, Akt and Bad. While in the presence of wortmannin (1 μM), a PI3K inhibitor, the gastrin-induced phosphorylation of Akt after H/R treatment was blocked. Additionally, wortmannin and Akt inhibitor VIII blocked the protective effect of gastrin on viability of HK-2 cells subjected to H/R treatment. These studies reveals that gastrin attenuates kidney I/R injury via a PI3K/Akt/Bad-mediated anti-apoptosis signaling. Thus, gastrin can be considered as a promising drug candidate to prevent AKI.

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

“…The PI3K/Akt-signaling pathway has been shown to play a vital role in survival signals in several neuronal cell types [ 19 , 64 , 65 ]. The function of Akt on cell survival signals has been linked to inhibiting the cytoplasmic cell death machinery and regulating the expression of genes involved in cell death and survival [ 64 , 65 ].…”

“…The PI3K/Akt-signaling pathway has been shown to play a vital role in survival signals in several neuronal cell types [ 19 , 64 , 65 ]. The function of Akt on cell survival signals has been linked to inhibiting the cytoplasmic cell death machinery and regulating the expression of genes involved in cell death and survival [ 64 , 65 ]. The PI3K/Akt-signaling pathway involved in the protective role against Aβ toxicity has been found associated with many natural compounds and antioxidant reagents, such as salidroside [ 66 ] and nitroso glutathione [ 27 ].…”

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine‐induced nephrotoxicity: Targeting Nrf2/HO‐1 and AKT/eNOS/NO pathways

“…The CsA‐evoked ROS production and diminished antioxidant defenses result in lowered mitochondrial membrane potential, increased mitochondrial pore permeability, and consequent release of the pro‐apoptotic cytochrome c to the intermembrane space, thereby, triggering the apoptotic machinery. In the context of apoptosis, phosphoinositide‐3‐kinase (PI3K)/protein kinase B (AKT) pathway has been characterized as a prosurvival pathway that orchestrates cellular growth and survival (Liu et al., 2020). Notably, interventions that can activate the PI3K/AKT signaling have been reported to effectively dampen the apoptotic events and renal injury in several renal pathologies (Arab et al, 2018a,b; Liu et al., 2020).…”

“…In the context of apoptosis, phosphoinositide‐3‐kinase (PI3K)/protein kinase B (AKT) pathway has been characterized as a prosurvival pathway that orchestrates cellular growth and survival (Liu et al., 2020). Notably, interventions that can activate the PI3K/AKT signaling have been reported to effectively dampen the apoptotic events and renal injury in several renal pathologies (Arab et al, 2018a,b; Liu et al., 2020). The PI3K/AKT pathway has been reported to counteract endothelial cell apoptosis via upregulation of endothelial nitric oxide synthase (eNOS) that generates the vasodilator nitric oxide (Hasan et al., 2020).…”

Lactobacillus acidophilus ATCC 4356 Alleviates Renal Ischemia–Reperfusion Injury Through Antioxidant Stress and Anti-inflammatory Responses and Improves Intestinal Microbial Distribution

“…Similarly, nobiletin inhibited inflammatory cytokines and regulated inducible nitric oxide synthase (iNOS)–endothelial nitric oxide synthase (eNOS) expression, thereby protecting rats from renal IRI ( 8 ). Gastrin attenuated renal IRI by anti-apoptosis ( 9 ). Congruously, our previous results have indicated that anti-oxidative stress could alleviate renal IRI.…”