Protective Effect of Klotho against Ischemic Brain Injury Is Associated with Inhibition of RIG-I/NF-κB Signaling

Abstract

Aging is the greatest independent risk factor for the occurrence of stroke and poor outcomes, at least partially through progressive increases in oxidative stress and inflammation with advanced age. Klotho is an antiaging gene, the expression of which declines with age. Klotho may protect against neuronal oxidative damage that is induced by glutamate. The present study investigated the effects of Klotho overexpression and knockdown by an intracerebroventricular injection of a lentiviral vector that encoded murine Klotho (LV-KL) or rat Klotho short-hairpin RNA (LV-KL shRNA) on cerebral ischemia injury and the underlying anti-neuroinflammatory mechanism. The overexpression of Klotho induced by LV-KL significantly improved neurobehavioral deficits and increased the number of live neurons in the hippocampal CA1 and caudate putamen subregions 72 h after cerebral hypoperfusion that was induced by transient bilateral common carotid artery occlusion (2VO) in mice. The overexpression of Klotho significantly decreased the immunoreactivity of glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1, the expression of retinoic-acid-inducible gene-I, the nuclear translocation of nuclear factor-κB, and the production of proinflammatory cytokines (tumor necrosis factor α and interleukin-6) in 2VO mice. The knockdown of Klotho mediated by LV-KL shRNA in the brain exacerbated neurological dysfunction and cerebral infarct after 22 h of reperfusion following 2 h middle cerebral artery occlusion in rats. These findings suggest that Klotho itself or enhancers of Klotho may compensate for its aging-related decline, thus providing a promising therapeutic approach for acute ischemic stroke during advanced age.

Ameliorating Effect of Klotho Protein on Rat Heart during I/R Injury

“…Moreover, the magnitude of damage and the number of dead cells were significantly lower after supplementation of the cardiac muscle with Klotho. These data were confirmed in other studies showing that Klotho prevents cell apoptosis and cytotoxic activity after induced oxidative stress in other organs [ 9 , 11 , 27 – 29 ]. Klotho also reduced the apoptosis in an animal model of I/R kidney injury or in a mouse kidney cell line after exposure to hydrogen peroxide [ 10 , 27 , 30 ].…”

“…Similarly, the level of necroptotic markers after renal I/R injury in mice was ameliorated by Klotho due to oxidative stress inhibition [ 31 ]. There was also a correlation of the neuroprotection and inhibition of neuropathological changes with the induced expression of Klotho after ischaemic injury in the murine brain [ 11 ]. Finally, the apoptosis and heart damage caused by endotoxemia or hyperglycaemia in mice were alleviated by Klotho [ 17 , 32 ].…”

“…Importantly, intracellular Klotho served as an endogenous anti-inflammatory and antiaging factor [ 6 , 7 ]. It has been shown that Klotho was involved in the kidney or brain protection by regulation of oxidative stress, inflammation, and apoptosis [ 5 , 9 – 11 ]. Moreover, Klotho deficiency correlated with the occurrence and development of atherosclerosis, coronary artery disease, myocardial infarction, and left ventricular hypertrophy [ 7 ].…”

Disease-modifying antirheumatic drugs and remote ischemic postconditioning ameliorate the myocardial injury in rats under cerebral stroke

“…However, it may manipulate the atherosclerotic lesion resulting in the risk of coronary microembolization (16). Therefore, in our study, we induced postconditioning in the lower extremity skeletal muscle to avoid potential embolization of possible atherosclerotic lesions in the coronary vessels (11).…”

“…Thirty-two rats were randomly divided into 4 groups, with 8 rats per group. The model of global cerebral ischemia was induced by the occlusion of bilateral common carotid arteries as previously described by Zhou et al (11). Rats were placed on the operation table in the supine position after being anesthetized with ketamine HCl (80 mg/kg) and xylazine (10 mg/kg).…”