Ischemia/reperfusion injury (IRI), the most common cause of acute kidney injury (AKI), is correlated with oxidative stress and subsequent inflammation. Taraxasterol, a natural product, has been shown to exert anti-oxidative and anti-inflammatory effects. However, the role of taraxasterol in renal IRI remains unknown. In this study, mice were subjected to 30 min of bilateral renal ischemia-reperfusion to induce AKI. Cellular hypoxia/reoxygenation (H/R) was used to mimic IRI in vitro. Western blotting, immunochemistry, immunofluorescence, TUNEL staining, ELISA, and flow cytometry were performed to evaluate kidney damage, oxidative stress, inflammation, and apoptosis in vivo and in vitro. Treatment with taraxasterol attenuated the following in a dose-dependent manner: tubular damage; infiltration of F4/80-positive macrophages; renal interstitial fibrosis; myeloperoxidase (MPO) activity; and expression of the inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). Moreover, taraxasterol treatment remarkably ameliorated apoptosis in the kidney by decreasing Bax expression and conserving Bcl2. Notably, MitoSOX assay revealed that treatment with taraxasterol suppressed the production of mitochondrial reactive oxygen species. Furthermore, taraxasterol suppressed phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) signaling pathways in vivo and in vitro. In conclusion, these findings indicate that taraxasterol has a protective effect on IRI-induced AKI via inhibition of oxidative stress, inflammation, and apoptosis.

Background: Aberrant DNA methylation patterns, including hypermethylation of key genes that inhibit fibrosis and inflammation, have been described in human kidney diseases. However, the role of DNA methyltransferase 1 (DNMT1) in hepatitis B virus-associated glomerulonephritis (HBV-GN) remains unclear. Methods: We explored the underlying mechanism by establishing HBV X protein (HBx) overexpressing renal tubular epithelial (HK-2) cells and human podocytes with DNMT1 knockdown. Using RNA-sequencing to determine the downstream targets of DNMT1 and evaluate its levels of promoter methylation. HBV transgenic mice were used to examine the effects of DNMT1 inhibitor on renal in vivo. Results: DNMT1 was significantly upregulated in the renal tissue of HBV-GN patients, accompanied by injuries of HK-2 cells and podocytes. HBx markedly upregulated DNMT1 and induced epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells and human podocytes. This increased DNMT1 expression was attenuated after DNMT1 knockdown, accompanied by restored HK-2 cells and podocyte injuries resulting from the activation of PI3K/Akt/mTOR and nuclear factor-kappa B (NF-κB) pathways. Hypermethylation of the phosphatase and tensin homolog (PTEN) promoter and vitamin D receptor (VDR) was induced in HBx-overexpressing HK-2 cells and podocytes, respectively, whereas DNMT1 knockdown effectively corrected these alterations. Furthermore, PTEN and VDR ablation resulted in marked EMT and inflammation induction in HBx-overexpressing HK-2 cells and human podocytes even with DNMT1 knockdown. Downregulation of the PI3K/Akt/mTOR-related pathway attenuated HBx-induced EMT and inflammation in HK-2 cells. Luciferase reporter assay revealed VDR as a direct target of the Snail family transcriptional repressor 1 (SNAI1) in HBx-overexpressing podocytes. DNA methylation inhibitor 5-azacytidine alleviated urinary protein and renal inflammation in HBV transgenic mice via PTEN-PI3K/Akt signaling and VDR signaling axis. Conclusions: Our study clarifies the potential epigenetic mechanisms underlying HBx-induced renal injuries in HBV-GN and the renoprotective effects of inhibiting DNMT1, which can provide important insights into the development of treatments for HBV-GN.

Background: Glucose degradation products (GDPs) in peritoneal dialysis (PD) solution (PDS) have been shown to inflict damage to the kidney, which is the major organ for advanced glycosylation end product elimination. Hence, this study investigated whether new PDSs with neutral pH and low-GDPs have a beneficial effect on the preservation of residual renal function (RRF) among PD patients. Methods: Randomized controlled trials examining the effect of neutral pH and low-GDP PDSs on RRF in PD patients >18 years old compared with conventional PDSs were selected. The modality of PD treatment was continuous ambulatory PD. The primary outcome variable was mean RRF value. Weekly Kt/V, urine volume, peritoneal ultrafiltration, blood pressure and all-cause mortality of PD patients were measured as secondary outcome variables. Results: We identified 6 randomized controlled trials and found that patients using low-GDP PDSs had a much slower rate of RRF loss compared with patients using conventional PDSs [mean difference (MD) = 0.45, 95% confidence intervals (CI) 0.10-0.80, p = 0.01]. In addition, weekly Kt/V was markedly improved in the low-GDP PDS group (MD = 0.13, 95% CI 0.06-0.21, p = 0.0005), and urine volume was increased (MD = 110.34, 95% CI 8.58-212.10, p = 0.03). No significant differences were observed between the two groups with respect to peritoneal ultrafiltration, blood pressure and risk of all-cause mortality. Conclusion: Our meta-analysis demonstrates a significant benefit of using low-GDP PDSs for RRF preservation in PD patients. Further trials are needed to determine whether this beneficial effect can affect long-term clinical outcomes.

There have been conflicting reports on the use of statins for prevention of contrast-induced nephropathy (CIN). The aim of this study was to assess the effectiveness of short-term (2 - 7 days), high-dose (80 mg/d) statins in the prevention of CIN. STUDY DESIGN, SETTING AND PARTICIPANTS: Randomized controlled trials assessing the preventive effect of short-term, highdose statins on CIN (published from 1966 to 2010) were searched. Quality of the trials was evaluated with the assessing risk of bias in studies included in the Cochrane reviews. CIN is the primary endpoint of the study. Meta-regression and a fixed-effects model were used for analyses. Five trials with a total of 1,009 patients were identified, with the overall effect of statins showing benefit for preventing CIN (relative risk (RR) = 0.53, 0.32 - 0.87). Meta-regression showed the existence of minor heterogeneity (I² = 19%) could be largely accounted for by baseline serum creatinine. Two studies conducted in patients with CKD Stage ≥ 3 did not reveal a statistically significant difference in CIN incidence between the statin and placebo groups (6.5% vs. 7.2%) (RR = 0.89, 0.46 - 1.73), without evidence of heterogeneity (I² = 0%, p = 0.79). The remaining three studies conducted in patients with CKD Stage > 3 revealed a significantly lower CIN incidence in the statin groups (3.6% vs. 11.9%) (RR = 0.28, 0.13 - 0.62), without evidence of heterogeneity (I2 = 0%, p = 0.87). The overall effect of shortterm, high-dose statin treatment seems to be helpful for prevention of CIN. However, the subgroup analysis shows statin benefit only in patients with CKD Stage > 3, but not in patients with CKD Stage ≤ 3. The relative low quality of the individual studies and limited studies means that only a limited conclusion on the use of statin for prevention of CIN was possible.

Scleroderma renal crisis (SRC) is an acute life-threatening manifestation of systemic sclerosis (SSc) caused by obliterative vasculopathy and thrombotic microangiopathy. Evidence suggests a pathogenic role of immunoglobulin G (IgG) targeting G-protein coupled receptors (GPCR). We therefore dissected SRC-associated vascular obliteration and investigated the specific effects of patient-derived IgG directed against angiotensin II type 1 (AT₁R) and endothelin-1 type A receptors (ET_AR) on downstream signaling events and endothelial cell proliferation. SRC-IgG triggered endothelial cell proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway and subsequent activation of the E26 transformation-specific-1 transcription factor (Ets-1). Either AT₁R or ET_AR receptor inhibitors/shRNA abrogated endothelial proliferation, confirming receptor activation and Ets-1 signaling involvement. Binding of Ets-1 to the tissue factor (TF) promoter exclusively induced TF. In addition, TF inhibition prevented endothelial cell proliferation. Thus, our data revealed a thus far unknown link between SRC-IgG-induced intracellular signaling, endothelial cell proliferation and active coagulation in the context of obliterative vasculopathy and SRC. Patients’ autoantibodies and their molecular effectors represent new therapeutic targets to address severe vascular complications in SSc.