Renoprotective effects of estrogen on acute kidney injury: the role of SIRT1

Acute kidney injury (AKI) is a common syndrome associated with high morbidity and mortality, despite progress in medical care. Many studies have shown that there are sex differences and different role of sex hormones particularly estrogens in kidney injury. In this regard, the incidence and rate of progression of kidney diseases are higher in men compared with women. These observations suggest that female sex hormone may be renoprotective. Silent information regulator 2 homolog 1 (SIRT1) is a histone deacetylase, which is implicated in multiple biologic processes in several organisms. In the kidneys, SIRT1 inhibits renal cell apoptosis, inflammation, and fibrosis. Studies have reported a link between SIRT1 and estrogen. In addition, SIRT1 regulates ERα expression and inhibition of SIRT1 activity suppresses ERα expression. This effect leads to inhibition of estrogen-responsive gene expression. In this text, we review the role of SIRT1 in mediating the protective effects of estrogen in the onset and progression of AKI.

     

Activators of SIRT1 in the kidney and protective effects of SIRT1 during acute kidney injury (AKI) (effect of SIRT1 activators on acute kidney injury)

Clinical and Experimental Nephrology - Acute kidney injury (AKI) is a complex disorder and a clinical condition characterized by acute reduction in renal function. If AKI is not treated, it can...     

Central mineralocorticoid receptors are indispensable for corticosterone-induced impairment of memory retrieval in rats

Previous studies indicated that stress levels of glucocorticoid hormones (cortisol in humans, and corticosterone in rodents) induce impairment of long-term memory retrieval, but the underlying mechanisms (genomic or nongenomic) are not clear. To clarify this issue, we investigated the involvement of brain corticosteroid receptors and protein synthesis in the corticosterone-induced impairment of memory retrieval. Young rats were trained in the water maze task with six trials per day for 6 consecutive days. Retention of the spatial training was assessed 24 h after the last training session with a 60-s probe trial. Experiments included intraventricular injections of anisomycin, a specific protein synthesis inhibitor or specific antagonists for both types of corticocosteroid receptors (mineralocorticoid receptor, MR, and glucocorticoids receptor, GR) before corticosterone administration shortly before retention testing. The results showed that administration of anisomycin did not change the corticosterone response. Administration of the MR, but not GR, antagonist blocked the corticosterone-induced response dose dependently. These findings provide evidence for the view that glucocorticoids impair memory retrieval through nongenomic mechanisms involving an interaction with central MRs.     

The effect of peripheral administration of growth hormone on AD-like cognitive deficiency in NBM-lesioned rats

Over-expression of blood–brain barrier P-glycoprotein is considered as a major hurdle in the treatment of various CNS disorders. A down-regulation strategy is considered as one means to counteract disease- or therapy-associated induction of P-glycoprotein. Here, we evaluated whether a targeting of P-glycoprotein can be achieved in mouse brain capillary endothelial cells using siRNA. A 4-day treatment paradigm with once daily hydrodynamic intravenous injections of siRNA resulted in a significant reduction of the P-glycoprotein-labeled area in the hippocampal hilus and parietal cortex. P-glycoprotein expression proved to be down-regulated in these brain regions by 31 and 16%, respectively. An impact of siRNA administration on density of brain capillaries was excluded by quantification of the endothelial cell marker GLUT-1. In conclusion, the study provides first preliminary evidence that a down-regulation of P-glycoprotein can be achieved in brain capillary endothelial cells by administration of siRNA in vivo.     

Apelin-13 Protects the Brain Against Ischemic Reperfusion Injury and Cerebral Edema in a Transient Model of Focal Cerebral Ischemia

The adipocytokine apelin is a peptide that was isolated from a bovine stomach for the first time. This peptide and its receptor are abundantly expressed in the nervous and cardiovascular systems. According to previous studies, apelin-13 protects cardiomyocytes from ischemic injury as well as apoptosis. In addition, this peptide has a neuroprotective effect on hippocampal and cultured mouse cortical neurons against NMDA receptor-mediated excitotoxicity. The present study was conducted to determine whether apelin-13 provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and apelin-13 at doses of 25, 50, and 100 μg were injected intracerebroventriculary (ICV) at the beginning of ischemia. Infarct volume ,brain edema, motor dysfunction, and apoptosis were assessed 24 h after MCAO. Treatment with apelin-13 at doses of 50 and 100 μg ICV markedly reduced total infarct volumes by 45 and 55 %, respectively (P?P?>?0.05). In addition, apelin-13 at doses of 50 and 100 μg reduced brain edema (P?P?P?>?0.05).     

Nesfatin-1 Improve Spatial Memory Impairment Following Transient Global Cerebral Ischemia/Reperfusion via Inhibiting Microglial and Caspase-3 Activation

Nesfatin-1, a recently discovered peptide, is involved in important functions such as food intake regulation and energy homeostasis. Previous studies have demonstrated that it has protective effects following myocardial injury and also protects dopaminergic cells against neurotoxicity with the anti-inflammatory and anti-apoptotic mechanisms. In this study, we aimed to assay the neuroprotective effects of Nesfatin-1 after brain ischemia/reperfusion. Twenty-eight male Wistar rats were randomly selected and allocated in the form of four groups (sham, Nesfatin-1, ischemia, ischemia+Nesfatin-1). Ischemia was created by obstruction couple common carotid arteries in 20-min period. Saline as a vehicle and Nesfatin-1 (20 μg/kg, intraperitoneally) were injected at the time of reperfusion. Spatial memory performances were evaluated by the Morris water maze. The level of protein expression was determined by immunohistochemical and immunofluorescence staining. Nesfatin-1 significantly reduced caspase-3 (P?<?0.01) and microglial activation (P?<?0.01) and improved spatial memory impairments (P?<?0.05) induced by brain ischemia. Nesfatin-1 has significant neuroprotective effects and can be introduced as a therapeutic agent against cerebral ischemia-induced injuries.     

Characterization of the CA1 pyramidal neurons in rat model of hepatic cirrhosis: insights into their electrophysiological properties

Although the key contributors of altering neurological function in hepatic encephalopathy are relatively well known, the electrophysiological mechanism of CA1 damage, a key vulnerable area during hyperammonemia, have not yet been defined. Therefore, here we focus on the electrophysiological mechanisms of cognitive impairments following bile duct ligation (BDL). We performed patch-clamp recordings from the CA1 pyramidal neurons in hippocampus of male Wistar rats, which underwent sham or BDL surgery. A striking electrophysiological change of hippocampal neurons in experimental model of BDL was observed in the present study. Spontaneous firing frequency and rate of action potential (AP) rebound was decreased and afterhyperpolarization amplitude (AHP) was increased significantly in hippocampal cells of BDL animals compared to sham group. Together, the results suggest that altered intrinsic properties of the hippocampal neurons may contribute to the cognitive abnormalities during hepatic encephalopathy (HE), highlighting the electrophysiological mechanisms for providing new treatments against HE.

     

The role of erythropoietin in remote renal preconditioning on hippocampus ischemia/reperfusion injury

Remote ischemic preconditioning (RIPC) is an intriguing approach which exposes a remote organ/tissue to a non-lethal transient ischemia/reperfusion (I/R) in order to potentiate the resistance of the desired organ/tissue against the next unwanted I/R. It has been suggested that RIPC exerts its effect through neuronal and hormonal pathways. The underlying mechanisms of RIPC are obscure and should be elucidated. In this study, we induced RIPC in mice using 3 cycles of 5 min ischemia alternating with 5 min reperfusion of the left renal artery. Renal failure was induced in mice by intra-peritoneal (i.p.) injection of 200 mg/kg body weight of gentamicin twice per day for 4 consecutive days. Global hippocampal ischemia reperfusion (I/R) was performed by bilateral carotid artery occlusion for 20 min followed by reperfusion for 72 h. Moreover, the retention trial of passive avoidance test was determined 72 h after global ischemia. Histopathological changes of hippocampus neurons were observed using Nissl staining to detect neuronal loss. Finally, terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) was performed to assess the status of apoptotic cells in the hippocampus. The results of this study suggest that renal ischemic preconditioning is a good candidate for prevention of I/R-induced hippocampal injury. However, RRPC (remote renal preconditioning) failed to exert a neuroprotective effect in mice with renal failure (RF), indicating the probable role of a humoral factor which is released from kidneys in response to ischemia. In agreement with this hypothesis, treatment of mice with rhEPO (5000 IU/kg intraperitoneal) before induction of RRPC restored the neuroprotective effects of RRPC in RF mice. Accordingly, it is plausible to expect that erythropoietin is released from kidneys to act as a mediator for RRPC-induced neuroprotective effects. Renal ischemic preconditioning prevents I/R-induced hippocampal injury. In contrast, renal failure hampers protective effects of RRPC, while exogenous administration of erythropoietin (EPO) significantly prevents the inhibiting effects of renal failure.     

Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia

Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral ischemic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule(5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction th rough occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic exercise significantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre-ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration.     

Involvement of hypothalamic pituitary adrenal axis on the analgesic cross-tolerance between morphine and nifedipine

Bidirectional cross-tolerance develops between opioids and Ca(2+) channel blockers relating to their antinociceptive effects; however, the role of hypothalamic pituitary adrenal (HPA) axis on this action has not been elucidated yet. We examined the analgesic cross-tolerance between morphine and nifedipine, a dihydropyridine calcium channel blocker, in intact and adrenalectomized (ADX) rats and also evaluated modification of HPA activity during this phenomenon. The tail-flick test was used to assess the nociceptive threshold. The plasma level of corticosterone, as a marker of HPA function, was measured by radioimmunoassay. Our results showed that, in sham operated rats which were chronically treated with morphine, nifedipine failed to affect nociceptive threshold but it could induce significant antinociceptive effect in ADX morphine treated animals. This effect was reversed by corticosterone replacement. Furthermore, morphine could not induce analgesic effect either in sham operated or in ADX animals that received chronic nifedipine. Chronic morphine inhibited the effect of nifedipine on corticosterone secretion but nifedipine treatment had no effect on morphine-induced corticosterone secretion. Based on these results, we can conclude that HPA axis is involved in the induction of cross-tolerance between morphine and nifedipine due to chronic morphine and not nifedipine treatment.