Abstract Background At present, estimated glomerular filtration rate (eGFR) remains the most frequently utilized parameter in the evaluation of kidney injury severity. Numerous equations have been formulated based on serum creatinine (Scr) or serum cystatin C (Cysc) levels. However, there is a lack of consensus regarding the efficacy of these equations in assessing eGFR, particularly for elderly individuals in China. This study aimed to evaluate the applicability of the MDRD, MDRDc, CKD-EPI series, BIS1, and FAS equations within the Chinese elderly population. Methods A cohort of 298 elderly patients with measured GFR (mGFR) was enrolled. The patients were categorized into three subgroups based on their mGFR levels. The eGFR performance was examined, taking into account bias, interquartile range (IQR), accuracy P30, and root-mean-square error (RMSE). Bland–Altman plots were employed to verify the validity of eGFR. Results The participants had a median age of 71 years, with 167 (56.0%) being male. Overall, no significant differences in bias were observed among the seven equations ( P > 0.05). In terms of IQR, P30, and RMSE, the BIS1 equation demonstrated superior accuracy (14.61, 72.1%, and 13.53, respectively). When mGFR < 30 ml/min/1.73 m 2 , all equations underestimated the true GFR, with the highest accuracy reaching only 59%. Bland–Altman plots indicated that the BIS1 equation exhibited the highest accuracy, featuring a 95% confidence interval (CI) width of 52.37. Conclusions This study suggested that the BIS1 equation stands out as the most applicable for estimating GFR in Chinese elderly patients with normal renal function or only moderate decline. 2020NL-085-03, 2020.08.10, retrospectively registered.
Aquaporin 3 (AQP3) is an aquaglyceroporin which transports water, glycerol and small solutes across the plasma membrane. Its functions are not limited to fluid transport but also involve the regulation of cell proliferation, migration, skin hydration, wound healing and tumorigenesis. While AQP3 has been reported to play an important role in keratinocyte proliferation, its role in differentiation remains controversial. Our study demonstrated that the expression of AQP3 was regulated during differentiation and that it participated in keratinocyte differentiation control. We further revealed that AQP3 was a transcriptional target of Notch signaling, a critical pathway regulating keratinocyte differentiation and tumor suppression, and it regulated differentiation through a reciprocal negative feedback loop with Notch1. When the expression level of AQP3 was elevated, impaired barrier integrity and increased pro-inflammatory cytokine production ensued, mimicking the pathological conditions in Notch deficient mice and in atopic dermatitis. Dysregulation of AQP3 and Notch receptors has been reported in several skin diseases, including skin cancer. Our discovery of the novel AQP3-Notch1 axis may provide insight into epidermal homeostasis control and possible translational applications, including its potential use as a biomarker for molecular diagnosis in environmental studies.
Tubular cell apoptosis has been implicated in the development of ischemic renal failure. In in vitro models, ATP depletion-induced apoptosis of tubular cells is mediated by the intrinsic pathway involving Bax translocation, cytochrome c release, and caspase activation. While the apoptotic cascade has been delineated, much less is known about its regulation. The current study has examined the regulation of ATP depletion-induced tubular cell apoptosis by acidic pH, a common feature of tissue ischemia. Cultured renal tubular cells were subjected to 3 h of ATP depletion with azide and then recovered in full culture medium. The treatment led to apoptosis in approximately 40% of cells. Apoptosis was significantly reduced, if the pH of ATP depletion buffer was lowered from 7-7.4 to 6-6.5. This was accompanied by the inhibition of caspase activation. However, acidic pH did not prevent Bax translocation and oligomerization in mitochondria. Cytochrome c release from mitochondria was not blocked either, suggesting that acidic pH inhibited apoptosis at the postmitochondrial level. To determine the postmitochondrial events that were blocked by acidic pH, we conducted in vitro reconstitution experiments. Exogenous cytochrome c, when added into isolated cell cytosol, induced caspase activation. Such activation was abrogated, when pH during the reconstitution was lowered to 6 or 6.5. Nevertheless, acidic pH did not prevent the recruitment and association of caspase-9 by Apaf-1, as shown by coimmunoprecipitation. Together, this study demonstrated the inhibition of tubular cell apoptosis following ATP depletion by acidic pH. A critical step blocked by acidic pH seems to be caspase-9 activation in apoptosome.
Vitamin C (ascorbic acid; AA) and copper (Cu2+) are well used supplements with many health-promoting actions. However, when they are used in combination, the Fenton reaction occurs, leading to the formation of highly reactive hydroxyl radicals. Given that kidney is vulnerable to many toxicants including free radicals, we speculated that the in vivo administration of AA plus Cu2+ may cause oxidative kidney injury. The purpose of this study was to address this possibility. Mice were administered with AA and Cu2+, alone or in combination, via oral gavage once a day for various periods. Changes in the systemic oxidative status, as well renal structure and functions, were examined. The administration of AA plus Cu2+ elevated protein oxidation in serum, intestine, bladder, and kidney, as evidenced by the increased sulfenic acid formation and decreased level of free sulfhydryl groups (-SH). The systemic oxidative stress induced by AA plus Cu2+ was associated with a significant loss of renal function and structure, as indicated by the increased blood urea nitrogen (BUN), creatinine and urinary proteins, as well as glomerular and tubular cell injury. These effects of AA and Cu2+ were only observed when used in combination, and could be entirely prevented by thiol antioxidant NAC. Further analysis using cultured renal tubular epithelial cells revealed that AA plus Cu2+ caused cellular protein oxidation and cell death, which could be abolished by NAC and catalase. Moreover, coincubation of AA and Cu2+ led to H2O2 production. Collectively, our study revealed that a combined administration of AA and Cu2+ resulted in systemic oxidative stress and renal cell injury. As health-promoting supplements, AA and Cu2+ should not be used together.
Astrocytes become reactive following various brain insults; however, the functions of reactive astrocytes are poorly understood. Here, we show that reactive astrocytes function as phagocytes after transient ischemic injury and appear in a limited spatiotemporal pattern. Following transient brain ischemia, phagocytic astrocytes are observed within the ischemic penumbra region during the later stage of ischemia. However, phagocytic microglia are mainly observed within the ischemic core region during the earlier stage of ischemia. Phagocytic astrocytes upregulate ABCA1 and its pathway molecules, MEGF10 and GULP1, which are required for phagocytosis, and upregulation of ABCA1 alone is sufficient for enhancement of phagocytosis in vitro. Disrupting ABCA1 in reactive astrocytes result in fewer phagocytic inclusions after ischemia. Together, these findings suggest that astrocytes are transformed into a phagocytic phenotype as a result of increase in ABCA1 and its pathway molecules and contribute to remodeling of damaged tissues and penumbra networks.Astrocytic phagocytosis has been shown to play a role in synaptic pruning during development, but whether adult astrocytes possess phagocytic ability is unclear. Here the authors show that following brain ischemia, reactive astrocytes become phagocytic and engulf debris via the ABCA1 pathway.
Thiol antioxidants play important roles in cell and body defense against oxidative stress. In body fluid, albumin is the richest source of thiol antioxidants. One recent study showed that the reductive modification of thiol residues in albumin potentiated its antioxidative activity. Given that whey protein (WP) contains albumin and other thiol-active proteins, this property of WP could be exploited to develop novel thiol antioxidants. The aim of this study was to address this possibility. WP was reductively modified with dithiothreitol (DTT). The modified protein exhibited significantly elevated free sulfhydryl groups (-SH) and thiol antioxidative activity. It detoxified H2O2 and prevented H2O2-initiated protein oxidation and cell death in a -SH group-dependent way in vitro. In addition, it reacted with GSH/GSSG and altered the GSH/GSSG ratio via thiol-disulfide exchange. In vivo, oral administration of the reductively modified WP prevented oxidative stress and renal damage in a mouse model of renal injury caused by ischemia reperfusion. It significantly improved renal function, oxidation, inflammation, and cell injury. These protective effects were not observed in the WP control and were lost after blocking the -SH groups with maleimide. Furthermore, albumin, one of the ingredients of WP, also exhibited similar protective effects when reductively modified. In conclusion, the reductive modification of thiol residues in WP transformed it into a potent thiol antioxidant that protected kidneys from ischemia reperfusion injury. Given that oxidative stress underlies many life-threatening diseases, the reductively modified dietary protein could be used for the prevention and treatment of many oxidative-stress-related conditions, such as cardiovascular diseases, cancer, and aging.
Gut microbiota has been implicated in the initiation and progression of various diseases; however, the underlying mechanisms remain elusive and effective therapeutic strategies are scarce. In this study, we investigated the role and mechanisms of gut microbiota in TNBS-induced colitis and its associated kidney injury while evaluating the potential of dietary protein as a therapeutic intervention. The intrarectal administration of TNBS induced colitis in mice, concurrently with kidney damage. Interestingly, this effect was absent when TNBS was administered intraperitoneally, indicating a potential role of gut microbiota. Depletion of gut bacteria with antibiotics significantly attenuated the severity of TNBS-induced inflammation, oxidative damage, and tissue injury in the colon and kidneys. Mechanistic investigations using cultured colon epithelial cells and bone-marrow macrophages unveiled that TNBS induced cell oxidation, inflammation and injury, which was amplified by the bacterial component LPS and mitigated by thiol antioxidants. Importantly, in vivo administration of thiol-rich whey protein entirely prevented TNBS-induced colonic and kidney injury. Our findings suggest that gut bacteria significantly contribute to the initiation and progression of colitis and associated kidney injury, potentially through mechanisms involving LPS-induced exaggeration of oxidative cellular damage. Furthermore, our research highlights the potential of dietary thiol antioxidants as preventive and therapeutic interventions.
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