Relationships among the Dosage of Erythropoiesis-Stimulating Agents, Erythropoietin Resistance Index, and Mortality in Maintenance Hemodialysis Patients.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) constitute an important treatment option for anemia in hemodialysis (HD) patients. We investigated the relationships among the dosage of ESA, erythropoietin resistance index (ERI) scores, and mortality in Chinese MHD patients. METHODS: This multicenter observational retrospective study included MHD patients from 16 blood purification centers (n = 824) who underwent HD in 2011-2015 and were followed up until December 31, 2016. We collected demographic variables, HD parameters, laboratory values, and ESA dosages. Patients were grouped into quartiles according to ESA dosage to study the effect of ESA dosage on all-cause mortality. The ERI was calculated as follows: ESA (IU/week)/weight (kg)/hemoglobin levels (g/dL). We also compared outcomes among the patients stratified into quartiles according to ERI scores. We used the Cox proportional hazards model to measure the relationships between the ESA dosage, ERI scores, and all-cause mortality. Using propensity score matching, we compared mortality between groups according to ERI scores, classified as either > or ≤12.80. RESULTS: In total, 824 patients were enrolled in the study; 200 (24.3%) all-cause deaths occurred within the observation period. Kaplan-Meier analyses showed that patients administered high dosages of ESAs had significantly worse survival than those administered low dosages of ESAs. A multivariate Cox regression identified that high dosages of ESAs could significantly predict mortality (ESA dosage >10,000.0 IU/week, HR = 1.59, 95% confidence intervals (CIs) (1.04, 2.42), and p = 0.031). Our analysis also indicated a significant increase in the risk of mortality in patients with high ERI scores. Propensity score matching-analyses confirmed that ERI > 12.80 could significantly predict mortality (HR = 1.56, 95% CI [1.11, 2.18], and p = 0.010). CONCLUSIONS: Our data suggested that ESA dosages >10,000.0 IU/week in the first 3 months constitute an independent predictor of all-cause mortality among Chinese MHD patients. A higher degree of resistance to ESA was related to a higher risk of all-cause mortality.

Sulforaphane prevents type 2 diabetes-induced nephropathy via AMPK-mediated activation of lipid metabolic pathways and Nrf2 antioxidative function.

Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 2 diabetes (T2D) by up-regulating nuclear factor (erythroid-derived 2)-like 2 (Nrf2). AMP-activated protein kinase (AMPK) can attenuate the pathogenesis of DN by improving renal lipotoxicity along with the activation of Nrf2-mediated antioxidative signaling. Therefore, we investigated whether AMPKα2, the central subunit of AMPK in energy metabolism, is required for SFN protection against DN in T2D, and whether potential cross-talk occurs between AMPKα2 and Nrf2. AMPKα2 knockout (Ampkα2-/-) mice and wildtype (WT) mice were fed a high-fat diet (HFD) or a normal diet (ND) to induce insulin resistance, followed by streptozotocin (STZ) injection to induce hyperglycemia, as a T2D model. Both T2D and control mice were treated with SFN or vehicle for 3 months. At the end of the 3-month treatment, all mice were maintained only on HFD or ND for an additional 3 months without SFN treatment. Mice were killed at sixth month after T2D onset. Twenty-four-hour urine albumin at third and sixth months was significantly increased as renal dysfunction, along with significant renal pathological changes and biochemical changes including renal hypertrophy, oxidative damage, inflammation, and fibrosis in WT T2D mice, which were prevented by SFN in certain contexts, but not in Ampkα2-/- T2D mice. SFN prevention of T2D-induced renal lipotoxicity was associated with AMPK-mediated activation of lipid metabolism and Nrf2-dependent antioxidative function in WT mice, but not in SFN-treated Ampkα2-/- mice. Therefore, SFN prevention of DN is AMPKα2-mediated activation of probably both lipid metabolism and Nrf2 via AMPK/AKT/glycogen synthase kinase (GSK)-3ß/Src family tyrosine kinase (Fyn) pathways.

Serum elabela and apelin levels during different stages of chronic kidney disease.

PURPOSE: The association of serum elabela (ELA) and apelin with the progression of chronic kidney disease (CKD) is unknown. We determined if serum ELA and apelin levels were associated with CKD stage. METHODS: This observational study involved 60 CKD patients and 20 healthy, age-, race-, and gender-matched controls. The participants were grouped according to renal function as follows: normal control group, CKD1 group (stage-1 CKD, 20 patients), CKD3 group (stage-3 CKD, 20 patients), and CKD5 group (stage-5 CKD, 20 patients) in accordance with the Kidney Disease Outcomes - Quality Initiative criteria. We recorded the demographic, clinical, and biochemical data of all participants. Serum ELA and apelin levels were measured using commercially available enzyme-linked immunosorbent assays. RESULTS: Serum ELA levels gradually and significantly declined with decreases in the estimated glomerular filtration rate (eGFR). Serum ELA showed significant negative correlations with serum creatinine (r = -0.529, p < .001), blood urea nitrogen (r = -0.575, p < .001), systolic blood pressure (r = -0.455, p < .001), and diastolic blood pressure (r = -0.450, p < .001), and significant positive correlations with hemoglobin (r = 0.523, p < .001) and eGFR (r = 0.728, p < .001). Multiple regression analysis showed that eGFR independently influenced serum ELA levels. No significant association was found between serum apelin levels and CKD progression. CONCLUSION: In CKD patients, serum ELA levels decreased with decreasing eGFR. This finding may provide a new target for the prediction, diagnosis, and staging of CKD.

A simplified percutaneous technique for inserting Tenckhoff catheters for peritoneal dialysis.

AIM: Successful catheter implantation is highly essential for delivering effective peritoneal dialysis (PD). The aim of the present study was to describe a newly developed, minimally invasive percutaneous technique for providing safe, timely, and effective peritoneal catheter insertion and assess the long-term outcome. MATERIALS AND METHODS: 100 PD catheters were placed in 100 consecutive patients by a nephrologist using the modified percutaneous technique with a special trocar, from August 1, 2010 to December 31, 2011. The patients were followed up until October 31, 2015. Demographic and clinical features of study subjects, duration of hospital stay, follow-up time, complications, and catheter survival were assessed in all patients. RESULTS: The patient study group included 47 men and 53 women, with a mean age of 55.3 ± 13.7 years. The mean hospitalization time was 17.1 ± 8.6 days, and the mean duration of follow-up was 44.7 ± 15.1 months. 71 patients were still on continuous ambulatory peritoneal dialysis at the time of study completion. Peritonitis was the most common complication observed, with an incidence of 28%. None of the patients experienced surgical complications such as bleeding or incisional hernia. The mean catheter survival time was 57.0 ± 1.5 months. CONCLUSION: Peritoneal catheter placement using our modified percutaneous technique is simple, safe, minimally invasive, and efficient. It carried less morbidity with respect to bowel perforation, catheter-related infection, and exit-site leak.
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Diagnostic Value of Urinary miR-152-5p in Patients with IgA Nephropathy with Elevated Proteinuria Levels.

BACKGROUND: The current study aims to observe the correlation between the expression of miR-152-5p in urine samples and the condition of IgA nephropathy (IgAN). METHODS: From January 2017 to October 2017, 40 patients with IgAN, 10 patients with mild glomerular lesions, 10 patients with membranous proliferative glomerulonephritis type I, 10 patients with focal segmental glomeruloscle-rosis, 10 patients with Henoch-Schonlein purpura nephritis, and 10 patients with lupus nephritis. Meanwhile, 25 healthy controls were also included in the physical examination center of our hospital. The expression level of miR-152-5p was detected by RT-qPCR. The correlation between the expression level of miR-152-5p and patholog-ical Haas grading and urinary protein was analyzed. RESULTS: The expression level of miR-152-5p in IgA nephropathy patients was higher than that in other types of glomerulonephritis and healthy control group (p < 0.0001). Meanwhile, the level of miR-152-5p in IgAN patients with high score (p < 0.01) was significantly increased. Furthermore, the level of miR-152-5p was positively corre-lated with the level of urinary protein and the degree of renal pathological damage (r2 = 0.89, p < 0.01). CONCLUSIONS: The expression of urinary miR-152-5p is positively correlated with IgA nephropathy, which provides a new way for early diagnosis and treatment of IgA nephropathy with elevated proteinuria.

FFNT25 ameliorates unilateral ureteral obstruction-induced renal fibrosis.

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) patients who progress to end-stage renal disease (ESRD). With the increasing incidence of CKD, it is of importance to develop effective therapies that blunt development of renal fibrosis. FFNT25 is a newly developed molecular compound that could be used to prevent fibrosis. In this study, we administered FFNT25 to rats following unilateral ureteral obstruction (UUO) to investigate its anti-fibrosis mechanism. Thirty-two Sprague-Dawley rats were randomly divided into four groups: (1) control (normal rats), (2) sham-operated, (3) UUO-operated + vehicle, and (4) UUO-operated + FFNT25. Two weeks after UUO, the rats were gavaged with either FFNT25 (20.6 mg/kg/day) or vehicle for two weeks. Serum, urine, and kidney samples were collected at the end of the study. FFNT25 reduced levels of renal fibrosis and decreased mRNA and protein levels of extracellular matrix (ECM) markers α-smooth muscle actin (α-SMA) and plasminogen activator inhibitor-1 (PAI-1) following UUO compared to vehicle treatment (n = 8, p<.05). The current results indicate that FFNT25 can affect both the production and degradation of collagen fibers to reduce fibrosis.

Long Noncoding RNA Small Nucleolar RNA Host Gene 1 (SNHG1) Promotes Renal Cell Carcinoma Progression and Metastasis by Negatively Regulating miR-137.

BACKGROUND Data on the expression of RCC tissues from the GEO database and patient survival data from TCGA were used to explore the prognostic significance of long noncoding RNA SNHG1. SNHG1 has been reported to participate in the development of several cancers, but, the underlying mechanism of SNHG1 in renal cell carcinoma (RCC) has not been reported. The purpose of our study was to investigate the potential function of SNHG1 in RCC. MATERIAL AND METHODS The expression of SNHG1 in 40 cases of RCC and adjacent normal tissues and 5 cell lines was detected by qRT-PCR. Cell proliferation, Transwell assay, and Western blotting assay were carried out to investigate the biological function of SNHG1. A rescue experiment was performed to verify that miR-137 can partly impede the effect of SNHG1 on renal cancer cells. RESULTS SNHG1 was identified to be overexpressed in RCC tissues and RCC cell lines. High levels of SNHG1 were correlated with poor prognosis of RCC patients. Knockdown of SNHG1 suppressed the proliferation, invasion, and EMT capacity in RCC. Moreover, miR-137 abrogated the effect of SNHG1 on RCC. CONCLUSIONS SNHG1 is significantly upregulated in RCC and renal cancer cell lines. Overexpression of SNHG1 participates in RCC tumorigenesis by regulating miR-137.

Efficacy and safety of mycophenolate mofetil in patients with IgA nephropathy: an update meta-analysis.

BACKGROUND: The application of mycophenolate mofetil (MMF) in treating patients with immunoglobulin A nephropathy (IgAN) remains uncertain. This update meta-analysis was performed to re-evaluate the therapeutic potential of MMF in IgAN. METHODS: Articles were obtained by searching the electronic databases without language restriction. Randomized controlled trials studying the role of MMF in treating IgAN were collected. The quality of included studies was critically evaluated. Data analyses were performed by using RevMan 5.3 software. RESULTS: A total of 297 articles were screened and eight articles were finally included. Among the eight randomized controlled trials, five and three were high quality and low quality, respectively. Both fixed-effect and random-effect model were used. Pooled results by combining all the eight studies suggested that IgAN patients in MMF group had a higher remission rate than that in control group. Compared to placebo or corticosteroid monotherapy, MMF monotherapy exerted a higher remission rate and side effect rate in both main analysis and subgroup analysis by human race. Compared to corticosteroid plus other immunosuppressive agent therapy, corticosteroid plus MMF therapy had a higher remission rate, lower serum creatinine doubling rate, progression to end-stage renal disease rate and side effects rate. Subgroup analysis by therapeutic regimen further confirmed these results between corticosteroid plus MMF therapy and corticosteroid plus cyclophosphamide therapy. Funnel-plot displayed a symmetrical figure, indicating no publication bias existed. CONCLUSIONS: MMF has the potential in treatment of IgAN, especially for Asians. The evidence currently available shows that MMF monotherapy has a more efficacy but higher side effects when compared to placebo or corticosteroid monotherapy in treatment of Asians with IgAN. While MMF combined with corticosteroid regimen has a more efficacy and lower side effects when compared with corticosteroid plus cyclophosphamide regimen.

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21.

AIMS/HYPOTHESIS: Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. METHODS: Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). RESULTS: Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. CONCLUSIONS/INTERPRETATION: The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.

Genetic variants of nuclear factor erythroid-derived 2-like 2 associated with the complications in Han descents with type 2 diabetes mellitus of Northeast China.

The transcription factor nuclear factor erythroid 2-like 2 (NFE2L2) is essential for preventing type 2 diabetes mellitus (T2DM)-induced complications in animal models. This case and control study assessed genetic variants of NFE2L2 for associations with T2DM and its complications in Han Chinese volunteers. T2DM patients with (n = 214) or without (n = 236) complications, or healthy controls (n = 359), were genotyped for six NFE2L2 single nucleotide polymorphisms (SNPs: rs2364723, rs13001694, rs10497511, rs1806649, rs1962142 and rs6726395) with TaqMan Pre-Designed SNP Genotyping and Sequence System. Serum levels of heme oxygenase-1 (HMOX1) were determined through enzyme-linked immunosorbent assay. Informative data were obtained for 341 cases and 266 controls. Between T2DM patients and controls, the genotypic and allelic frequencies and haplotypes of the SNPs were similar. However, there was a significant difference in genotypic and allelic frequencies of rs2364723, rs10497511, rs1962142 and rs6726395 between T2DM patients with and without complications, including peripheral neuropathy, nephropathy, retinopathy, foot ulcers and microangiopathy. Furthermore, HMOX1 levels were significantly higher in T2DM patients with complications than in controls. Multiple logistic regression analysis, however, showed that only rs2364723 significantly reduced levels of serum HMOX1 in T2DM patients for the GG genotype carriers compared with participants with CG+CC genotype. The data suggest that although NFE2L2 rs2364723, rs10497511, rs1962142 and rs6726395 were not associated with T2DM risk, they were significantly associated with complications of T2DM. In addition, only for rs2364723 higher serum HMOX1 levels were found in the T2DM patients with CG+CC than those with GG genotype.

Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation.

Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation.

A porcine model of relief of unilateral ureteral obstruction: study on self-repairing capability over multiple time points.

It is still controversial whether renal tubular interstitial fibrosis (TIF) is a reversible process. Although previous studies examining TIF have been carried out in rodents, their kidney size and physiological character differ with humans, and the difference among diverse individuals before and after damage was obvious. Thus an experimental animal model to simulate human kidney disease was urged to be established. In order to clarify whether TIF is reversible, and the exact time points that the kidney has the capacity to be repaired, a porcine relief of unilateral ureteral obstruction (R-UUO) model was developed. Kidney damage and reparation were observed dynamically in vivo over various time points. Pigs were randomized divided into three groups (n = 6): UUO 5 days group, UUO 7 days, and UUO 10 days group. Each porcine in that groups underwent UUO and subsequent R-UUO for three time points. Renal function, histological structure, and protein expressions of α-smooth muscle actin (α-SMA), vimentin and E-cadherin were evaluated at different time points. Following R-UUO after 5 and 7 days of UUO, compared to UUO, serum creatinine levels were significantly decreased. Renal pathological tissue damage was repaired. The expressions of α-SMA and vimentin were decreased and E-cadherin expression was increased (P < 0.05). However, during R-UUO 14, 28, and 56 days after 10 days of UUO, serum creatinine was not decreased significantly. The expressions of α-SMA and vimentin consistently remained at high levels. Renal damage was unable to be restored and resulted in chronic lesions. Kidney damage induced by UUO can be reversed in early stages. However, longer time of UUO with significant levels of TIF showed limited reversibility. The porcine R-UUO model provides an ideal animal model for the investigation of kidney injury and repair as well as for the evaluation of the effect of drug treatment.

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.

BACKGROUND: Treatment of lupus nephritis (LN) remains challenging. OBJECTIVE: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN. DESIGN: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616). SETTING: 26 renal centers in China. PATIENTS: Adults (aged 18 to 65 years) with biopsy-proven LN. INTERVENTION: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy. MEASUREMENTS: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events. RESULTS: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]). LIMITATION: The study was limited to 24 weeks of follow-up. CONCLUSION: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN. PRIMARY FUNDING SOURCE: National Basic Research Program of China, National Key Technology R&D Program.

Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.

Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.

Sirtuin 1: A Target for Kidney Diseases.

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent histone deacetylase that is necessary for caloric restriction-related lifespan extension. SIRT1, as an intracellular energy sensor, detects the concentration of intracellular NAD(+) and uses this information to adapt cellular energy output to cellular energy requirements. Previous studies on SIRT1 have confirmed its beneficial effects on cellular immunity to oxidative stress, reduction of fibrosis, suppression of inflammation, inhibition of apoptosis, regulation of metabolism, induction of autophagy and regulation of blood pressure. All of the above biological processes are involved in the pathogenesis of kidney diseases. Therefore, the activation of SIRT1 may become a therapeutic target to improve the clinical outcome of kidney diseases. In this review, we give an overview of SIRT1 and its molecular targets as well as SIRT1-modulated biological processes, with a particular focus on the role of SIRT1 in kidney diseases.

Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition.

Increasing evidence from human and laboratory studies showed the effect of zinc (Zn) on diabetic complications. Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays important role in the prevention of oxidative damage. This study was to define whether Zn statues (deficiency or supplement) affect the Nrf2 expression and function, and also affect the damage severity of human renal tubular (HK11) cells exposed to high glucose (HG) with palmitate (Pal) and kidney of diabetic mice induced by multiple low-dose streptozotocins. For Zn deficiency diabetic mice were treated with Zn chelator PTEN at 5 mg/kg bw daily for 4 months. Results showed that HG/Pal significantly increased the expression of pro-fibrotic mediators, connective tissue growth factor and PAI-1, in HK11 cells, which was exacerbated by TPEN that depleted intracellular free Zn and decreased Nrf2 expression and transcription. Zn supplement prevented the effects of TPEN and also increased Akt and GSK-3ß phosphorylation with a decrease in Nrf2 nuclear exporter, Fyn. All these effects of Zn were abolished by Akt inhibitor. Therefore, Zn up-regulates Nrf2 function via activating Akt-mediated inhibition of Fyn function. Treatment of diabetic mice with TPEN decreased renal Zn level and Nrf2 expression and transcription, with an exacerbation of renal oxidative damage, inflammation and fibrosis. These results suggest the essentiality of Zn for Nrf2 expression and transcription function.

Inhibition of MAPK-mediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy.

A range of in vitro, experimental and clinical intervention studies have implicated an important role for hyperglycaemia-induced activation of the renin-angiotensin system (RAS) in the development and progression of diabetic nephropathy (DN). Blockade of RAS by angiotensin converting enzyme (ACE) inhibitors is an effective strategy in treating diabetic kidney diseases. However, few studies demonstrate the mechanism by which hyperglycaemia up-regulates the expression of ACE gene. Our previous studies have identified a novel curcumin analogue, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66), which could inhibit the high glucose (HG)-induced phosphorylation of mitogen-activated protein kinases in mouse macrophages. In this study, we found that the renal protection of C66 in diabetic mice was associated with mitogen-activated protein kinase (MAPK) inactivation and ACE/angiotensin II (Ang II) down-regulation. Generally, MAPKs have been considered as a downstream signalling of Ang II and a mediator for Ang II-induced pathophysiological actions. However, using C66 and specific inhibitors as small molecule probes, in vitro experiments demonstrate that the MAPK signalling pathway regulates ACE expression under HG stimulation, which contributes to renal Ang II activation and the development of DN. This study indicates that C66 is a potential candidate of DN therapeutic agents, and more importantly, that reduction in ACE expression by MAPKs inhibition seems to be an alternative strategy for the treatment of DN.

Efficacy and safety of Abelmoschus manihot for primary glomerular disease: a prospective, multicenter randomized controlled clinical trial.

BACKGROUND: Abelmoschus manihot, a single medicament of traditional Chinese medicine, has been widely used to treat kidney disease. This is the first randomized controlled clinical trial to assess its efficacy and safety in patients with primary glomerular disease. STUDY DESIGN: Prospective, open-label, multicenter, randomized, controlled, clinical trial. SETTING & PARTICIPANTS: From May 2010 to October 2011, a total of 417 patients with biopsy-proven primary glomerular disease from 26 hospitals participated in the study. INTERVENTIONS: A manihot in the form of a huangkui capsule, 2.5 g, 3 times per day; losartan potassium, 50mg/d; or combined treatment, a huangkui capsule at 2.5 g 3 times per day, was combined with losartan potassium, 50mg/d. The duration of intervention was 24 weeks. OUTCOMES & MEASUREMENTS: The primary outcome was change in 24-hour proteinuria from baseline after treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after treatment was a secondary outcome. The 24-hour proteinuria was measured every 4 weeks and eGFR was measured at 0, 4, 12, and 24 weeks. RESULTS: Mean baseline urine protein excretion was 1,045, 1,084, and 1,073 mg/d in the A manihot, losartan, and combined groups, respectively, and mean eGFR was 108, 106, and 106 mL/min/1.73 m2, respectively. After 24 weeks of treatment, mean changes in proteinuria were protein excretion of -508, -376, and -545 mg/d, respectively (P=0.003 for A manihot vs losartan and P<0.001 for the combined treatment vs losartan). Mean eGFR did not change significantly. The incidence of adverse reactions was not different among the 3 groups (P>0.05), and there were no severe adverse events in any group. LIMITATIONS: Results cannot be generalized to those with nephrotic syndrome or reduced eGFR. CONCLUSIONS: A manihot is a promising therapy for patients with primary kidney disease (chronic kidney disease stages 1-2) with moderate proteinuria.

[Retracted] MicroRNA­320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1.

Subsequently to the publication of the above paper, the authors drew to the attention of the Editorial Office that they made a couple of errors in terms of the data assembly in Figs. 2 and 4 in their paper; specifically, the Transwell assay data shown for the 'miR-320a+/FoxM1+' panel in Fig. 5D on p. 1923 also appeared as the 'ACTN/NC' data panel in Fig. 4E on the same page (Fig. 4E contained the erroneously duplicated panel). In addition, data featured in Fig. 2D of the above paper were strikingly similar to data that appeared in Fig. 6e of the following paper, published subsequently to this article, written by different authors (although a Dr Shiyue Zhao worked in the molecular biology laboratory of Harbin Medical University from 2017 to 2018, and the research collaboration was conducted with Dr Chenlong Li's research group): Li C, Zheng H, Hou W, Bao H, Xiong J, Che W, Gu Y, Sun H and Liang P: Long non-coding RNA linc00645 promotes. TGF-ß-induced epithelial-mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma. Cell Death Dis 10: 17, 2019. Finally, after having conducted an independent investigation of the data in this paper, the Editorial Office noted that one of the Petri dish images in Fig. 2C was also strikingly similar to data that appeared in Fig. 2H of the abovementioned article in the journal Cell Death & Disease. After having considered the authors' request for corrigendum, in view of the problems that were identified with the data, the Editor of Oncology Reports has decided that, owing to a lack of confidence in the presented data, the paper should instead be retracted from the journal. After having informed the authors of this decision, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused.  [Oncology Reports 40: 1917­1926, 2018; DOI: 10.3892/or.2018.6597].

Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice.

Oxidative stress is a major cause of diabetic nephropathy. Upregulation of the key antioxidative transcription factor, nuclear factor-erythroid 2-related factor 2 (Nrf2), was found to prevent the development of diabetic nephropathy. The present study was designed to explore the therapeutic effect of Nrf2 induced by proteasomal inhibitor MG132 at a low dose (10 µg/kg) on diabetic nephropathy. Transgenic type 1 diabetic (OVE26) mice displayed renal dysfunction with albuminuria by 3 mo of age, at which time MG132 treatment was started. After 3-mo treatment with MG132, renal function, morphology, and biochemical changes were examined with real-time PCR, Western blotting, and immunohistochemical examination. Compared with age-matched, nontreated diabetic mice, MG132-treated diabetic mice showed significant improvements in terms of renal structural and functional alterations. These therapeutic effects were associated with increased Nrf2 expression and transcriptional upregulation of Nrf2-regulated antioxidants. Mechanistic study using human renal tubular HK11 cells confirmed the role of Nrf2, as silencing the Nrf2 gene with its specific siRNA abolished MG132 prevention of high-glucose-induced profibrotic response. Furthermore, diabetes was found to significantly increase proteasomal activity in the kidney, an effect that was significantly attenuated by 3 mo of treatment with MG132. These results suggest that MG132 upregulates Nrf2 function via inhibition of diabetes-increased proteasomal activity, which can provide the basis for the therapeutic effect of MG132 on the kidney against diabetes-induced oxidative damage, inflammation, fibrosis, and eventual dysfunction.