This study investigates the effects of bisphenol A (BPA) contamination on the kidney and the possible protection by melatonin in experimental rats and isolated mitochondrial models. Rats exposed to BPA (50, 100, and 150 mg/kg, i.p.) for 5 weeks demonstrated renal damages as evident by increased serum urea and creatinine and decreased creatinine clearance, together with the presence of proteinuria and glomerular injuries in a dose-dependent manner. These changes were associated with increased lipid peroxidation and decreased antioxidant glutathione and superoxide dismutase. Mitochondrial dysfunction was also evident as indicated by increased reactive oxygen species production, decreased membrane potential change, and mitochondrial swelling. Coadministration of melatonin resulted in the reversal of all the changes caused by BPA. Studies using isolated mitochondria showed that BPA incubation produced dose-dependent impairment in mitochondrial function. Preincubation with melatonin was able to sustain mitochondrial function and architecture and decreases oxidative stress upon exposure to BPA. The findings indicated that BPA is capable of acting directly on the kidney mitochondria, causing mitochondrial oxidative stress, dysfunction, and subsequently, leading to whole organ damage. Emerging evidence further suggests the protective benefits of melatonin against BPA nephrotoxicity, which may be mediated, in part, by its ability to diminish oxidative stress and maintain redox equilibrium within the mitochondria.

Mitochondrial impairment ensuing from oxidative imbalance is related to adverse consequences of bisphenol A (BPA), a globally utilized industrial chemical. Recent evidence reveals sirtuin 3 (SIRT3) as a key regulator of mitochondrial homeostasis; however, its role in BPA toxicity remains unidentified. This study explored the potential benefits of N-acetylcysteine (NAC), an effective antioxidant, against BPA toxicity in the kidney and liver, and examined whether SIRT3 was involved in this condition. Male Wistar rats were fed with vehicle, BPA (5, 50 mg/kg), BPA (50 mg/kg) plus NAC (100 mg/kg) and were evaluated after 5 weeks. NAC treatment significantly diminished BPA-induced kidney and liver functional disorders, histopathological alterations, oxidative stress, and apoptosis. The increased mitochondrial reactive oxygen species, the disrupted membrane potential, the swelling, and the impaired mitochondrial fission caused by BPA were also mitigated upon concurrent treatment with NAC. The benefits of NAC were associated with enhanced AMPK-PGC-1α-SIRT3 signaling protein expressions, which led to decreased acetylation of superoxide dismutase 2 (SOD2) and increased expression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD). The findings demonstrate the efficacy of NAC in protecting BPA-induced kidney and liver injury, which, in part, is mediated by activating SIRT3 and improving mitochondrial function, dynamics, and oxidative imbalance.

Generation of toxic oxygen metabolites followed by oxidant- and inflammatory-mediated tissue injury plays a crucial role in the pathogenesis of ischemia and reperfusion (IR). Ubiquinol, the reduced form of coenzyme Q10, is recognized for its potent antioxidant and anti-inflammatory properties in biological membranes. The present study was established to examine the possible protective effect of ubiquinol against renal IR injury. Groups of male Wistar rats were assigned into sham, ubiquinol, IR (45-min bilateral renal ischemia followed by 24-h reperfusion), and ubiquinol+ IR (ubiquinol 300 mg/kg given orally for 7 consecutive days before IR induction). Renal morphology, function, oxidative stress, and inflammatory markers were evaluated at the end of reperfusion. IR caused renal dysfunction as shown by significant increases in blood urea nitrogen, plasma creatinine, and a decrease in creatinine clearance. Light and electron microscopic examinations exhibited severe tubular damages and abnormal mitochondrial structure. IR-induced renal injuries were associated with significant increases in malondialdehyde, nitric oxide, tumor necrosis factor-α, but decreases in antioxidant thiols and superoxide dismutase. Pretreatment with ubiquinol obviously attenuated all the changes caused by IR, whereas it had no considerable effect in the sham-operated rats. These findings indicate that supplementation of ubiquinol prior to IR incidence confers functional and morphological protection to the ischemic kidney by maintaining the redox balance and regulating the generation of inflammatory mediator. The outcomes suggest that ubiquinol may be a potential candidate to counteract organ dysfunction in conditions involving IR injury.

Nephrotoxicity is recognized as a serious disorder affected by chronic cadmium exposure. Imbalance between radical generation and elimination is considered a critical factor involved in the initiation and progression of renal injury caused by this heavy metal. The present study investigated the possible protection by catechin, a natural phenolic antioxidant, against cadmium nephrotoxicity and elucidated its potential mechanism. Male Wistar rats were assigned to receive vehicle, cadmium (CdCl 2 mg/kg, i.p.) and cadmium plus catechin (25, 50, and 100 mg/kg, orally, respectively). After 4 weeks of treatment, rats exposed to cadmium demonstrated a marked rise in blood urea nitrogen and creatinine, a fall in creatinine clearance, and renal pathologies like severe tubular damage, apoptosis, and abnormal mitochondrial structure. Significant increases in malondialdehyde, nitric oxide, and tumor necrosis factor-alpha, while reductions in antioxidant thiols, superoxide dismutase, and catalase, were also detected in the kidney tissues of cadmium-intoxicated rats. These alterations were associated with mitochondrial dysfunction as supported by an increase in mitochondrial reactive oxygen species production and a decline in mitochondrial membrane potential. Treatment with catechin significantly attenuated all the changes caused by cadmium. These findings suggest that catechin effectively protects the kidney against toxic effect of cadmium, presumably through its antioxidant, anti-inflammation, and mitochondrial protection. The study outcomes not only add evidence to reinforce the medical benefits of catechin but also, most importantly, give rise to a prospect of developing renal preventive strategy for individuals who are at risk of cadmium contamination by means of catechin supplementation.

Exposure to bisphenol A (BPA), a chemical generally used in consumer products, becomes a global public health concern, as humans are increasingly exposed through their daily consuming activities. Renal ischemia–reperfusion (RIR) is the major cause of acute kidney injury with high prevalence and increased long‐term risks for multiple comorbidities and mortality. As the kidney is susceptible to these conditions, we explored whether the outcomes following the RIR episode could be influenced by BPA exposure, and investigated the therapeutic possibility by N‐acetylcysteine (NAC) including the mechanisms involved. Three groups of male Wistar rats were fed with vehicle, BPA 5, and 50 mg/kg, respectively, for five consecutive weeks then underwent the sham operation. Three other groups with identical treatment underwent bilateral renal IR induction (45‐min ischemia followed by 24‐hr reperfusion). An additional RIR group was treated with BPA 50 plus NAC 100 mg/kg. BPA‐exposed rats that encountered RIR episode showed dose‐dependent worsening of RIR injury as evidenced by augmentations of renal dysfunction and histopathological abnormalities, oxidative stress, apoptosis, mitochondrial functional impairment, mitochondrial dynamic, and mitophagy disproportion compared with the vehicle‐exposed RIR group. The NAC therapy considerably attenuated the exacerbated effects of BPA, which was associated with increased AMP‐activated protein kinase (AMPK), PGC‐1α, silent information regulator 3 or sirtuin 3 (SIRT3), and mitofusin 2 (MFN2) expressions but decreased Phosphorylated dynamin‐related protein 1 (p‐DRP1)/Dynamin‐related protein 1 (DRP1), PTEN‐induced putative kinase (PINK), and PARKIN expressions. These findings reveal the detrimental effect of repeated BPA exposure on the renal outcomes following the IR episode, and further demonstrate the protective efficacy of NAC by maintaining mitochondrial homeostasis, which is, partly, mediated through the AMPK‐PGC‐1α‐SIRT3 axis.

The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic antiinflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the cAp protected the kidney even after injury in a cisplatin-induced nephropathy model. considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury. Despite the advancements in modern medical technology, acute kidney injury (AKI) is still one of the major comorbidities in hospital settings. It is estimated that AKI occurs in approximately 15% of hospitalized patients and 60% of critically ill patients 1 , and morbidity and mortality rates remain high 2,3. In addition, AKI is a risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD) 4. Therefore, prevention of AKI development and progression to CKD is essential. Inflammation plays an important role in the pathogenesis of AKI 5. Moreover, chronic inflammation contributes to the progression of CKD. Therefore, suppression of inflammation plays a potential role in treating kidney injury. Recently, a new anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) has been discovered 6. The CAP consists of both afferent and efferent arms, and both afferent and efferent vagus nerves play important roles. The afferent vagus nerve conducts inflammatory information from the peripheral organs to the central nervous system. In the brainstem, the afferent vagus nerve activates the C1 neurons, which make a major contribution to the central regulation of autonomic function 7 , and further stimulate the efferent vagus nerve 8. Previously, Inoue and Abe et al. reported that vagus nerve stimulation (VNS) protected the kidney from ischemia-reperfusion injury (IRI) through activation of the CAP 9. Although there are many kinds of inflammatory cells such as B cells, T cells, and dendritic cells ...

Distant organ liver damage after acute kidney injury (AKI) remains a serious clinical setting with high mortality. This undesirable outcome may be due to some hidden factors that can intensify the consequences of AKI. Exposure to bisphenol A (BPA), a universal chemical used in plastics industry, is currently unavoidable and can be harmful to the liver. This study explored whether BPA exposure could be a causative factor that increase severity of remote liver injury after AKI and examined the preventive benefit by N-acetylcysteine (NAC) in this complex condition. Male Wistar rats were given vehicle, BPA, or BPA + NAC for 5 weeks then underwent 45 min renal ischemia followed by 24 h reperfusion (RIR), a group of vehicle-sham-control was also included. RIR not only induced AKI but produced liver injury, triggered systemic oxidative stress as well as inflammation, which increasing severity upon exposure to BPA. Given NAC to BPA-exposed rats diminished the added-on effects of BPA on liver functional impairment, oxidative stress, inflammation, and apoptosis caused by AKI. NAC also mitigated the abnormalities in mitochondrial functions, dynamics, mitophagy, and ultrastructure of the liver by improving the mitochondrial homeostasis regulatory signaling AMPK-PGC-1α-SIRT3. The study demonstrates that NAC is an effective adjunct for preserving mitochondrial homeostasis and reducing remote effects of AKI in environments where BPA exposure is vulnerable.

BackgroundThe sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI).MethodsWe performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of β2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling.ResultsIn vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue.ConclusionsThe activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.