INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Jianan Yang,Tonglian Jiang,Xun Lu,Xiang li,Xuling Zhou,Xinxin Guo,Chengxin Ma,Xiaobei Xie,Dongxiao Li,Siqi Yu,Jiayi An,Binghai Zhao,Hongzhi Li
Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN.
研究领域:
肾病学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
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IF 5.6
Lijuan Ma,Xueqi Liu,Mengya Zhang,Lang Zhou,Ling Jiang,Li Gao,Xian Wang,Yuebo Huang,Hanxu Zeng,Yonggui Wu
The pathophysiological mechanism of acute kidney injury (AKI) is complicated, and effective drugs are still lacking. Ferroptosis is a newly discovered regulatory cell death mode characterized by the lethal accumulation of iron and reactive oxygen species-(ROS-)-dependent lipid hydroperoxides. In recent years, ferroptosis has been confirmed to be involved in the progression of AKI. Paeoniflorin (PF) is a traditional Chinese medicine that has protective effects on a variety of kidney diseases including AKI. However, the mechanism by which PF attenuates AKI is unclear. We detected that PF attenuated serum biochemical markers, histological damage, ferroptosis and inflammation in a dose-dependent manner in a mouse AKI model with bilateral renal artery ischemia–reperfusion (IR). Hypoxia-reoxygenation (HR)-induced ferroptosis and inflammation was also inhibited by PF in human renal tubular epithelial cells (HK2). RNA sequence analysis revealed that PF inhibited ferroptosis in HK2 cells by upregulating Slc7a11 in the glutathione pathway after HR treatment. PF failed to further protect cells with specific knockdown of Slc7a11 from ferroptosis under HR conditions. Consequently, these data indicated that PF prevention of ferroptosis in AKI requires dependence on Slc7a11. This study provided a scientific basis for the clinical search for drugs to prevent IR induced AKI.
研究领域:
药理学
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肾病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2016
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IF 3.847
Jean-Charles Gautier,Xiaobing Zhou,Yi Yang,Thierry Gury,Zhe Qu,Xavier Palazzi,Jean-François Léonard,Mohamed Slaoui,Yaligara Veeranagouda,Isabelle Guizon,Eric Boitier,Aziz Filali-Ansary,Bart H.J. van den Berg,Oliver Poetz,Thomas Joos,Tianyi Zhang,Jufeng Wang,Philippe Detilleux,Bo Li
Most studies to evaluate kidney safety biomarkers have been performed in rats. This study was conducted in Cynomolgus monkeys in order to evaluate the potential usefulness of novel biomarkers of nephrotoxicity in this species. Groups of 3 males were given daily intramuscular injections of gentamicin , a nephrotoxic agent known to produce lesions in proximal tubules, at dose-levels of 10, 25, or 50 mg/kg/day for 10 days. Blood and 16-h urine samples were collected on Days − 7, − 3, 2, 4, 7, and at the end of the dosing period. Several novel kidney safety biomarkers were evaluated, with single- and multiplex immunoassays and in immunoprecipitation-LC/MS assays, in parallel to histopathology and conventional clinical pathology parameters. Treatment with gentamicin induced a dose-dependent increase in kidney tubular cell degeneration/necrosis, ranging from minimal to mild severity at 10 mg/kg/day, moderate at 25 mg/kg/day, and to severe at 50 mg/kg/day. The results showed that the novel urinary biomarkers, microalbumin, α1-microglobulin, clusterin , and osteopontin , together with the more traditional clinical pathology parameters, urinary total protein and N-acetyl-β-D-glucosaminidase (NAG), were more sensitive than blood urea nitrogen (BUN) and serum creatinine (sCr) to detect kidney injury in the monkeys given 10 mg/kg/day gentamicin for 10 days, a dose leading to an exposure which is slightly higher than the desired therapeutic exposure in clinics. Therefore, these urinary biomarkers represent non-invasive biomarkers of proximal tubule injury in Cynomolgus monkeys which may be potentially useful in humans.
研究领域:
毒理学
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药理学
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临床研究
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
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2023
·Vol. 27
·期 2
·1-10
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IF 3.4
Cunyang Gu,Feng Gao,Shiqi Zhang,Lihua Kang,Wei Zhang,Xiaojuan Feng,Jinxi Liu,Yuexin Tian,Qun Wei,Yunxia Du,Yujia Xing,Qingjuan Liu,Shuxia Liu
Tubulointerstitial fibrosis (TIF) is an important pathological change that occurs during the development of diabetic kidney disease. The epithelial‑mesenchymal transition (EMT) of renal tubular epithelial cells is a manifestation of TIF. STAT1, a member of the STAT family of transcription factors, can be modified by the small ubiquitin‑related modifier (SUMO), thus affecting the activity of STAT1. The present study investigated the role of STAT1 SUMOylation in high glucose‑induced tubular EMT by western blotting, immunocytochemistry, immunofluorescence, co‑immunoprecipitation and dual luciferase reporter analysis. The results indicated that in the process of high glucose‑induced EMT, STAT1 activation protected the cells from EMT. However, high glucose also increased the SUMOylation of STAT1, which prevented STAT1 from exerting an effective protective role by inhibiting its activity.
研究领域:
分子生物学
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细胞生物学
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糖尿病研究
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肾病学
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产品关联
DOI
PubMed
高影响因子
PeerJ
·
2023
·
IF 2.7
Linlin Sun,Miao Ding,Fuhua Chen,Dingyu Zhu,Xinmiao Xie
Podocyte injury is a critical factor in the pathogenesis of diabeticnephropathy (DN). Emerging evidence has demonstrated that breviscapine (Bre) exerts a renoprotective effect on diabetic rats. However, the effects of Bre on regulating podocyte injury under high glucose (HG) conditions remain unclear. In this study, an experimental mouse model of DN was induced by intraperitoneal injections of streptozotocin (STZ) in vivo . The effects of Bre on podocyte injury were assessed using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTPnick-endlabelling (TUNEL) staining, quantitative real-time PCR (qRT‒PCR) and western blot analysis. We found that renal function was significantly decreased in diabetic mice, and this effect was blocked by Bre treatment. Bre effectively increased podocyte viability and inhibited HG-induced cell apoptosis. Furthermore, Bre ameliorated HG-induced podocyte injury, as evidenced by decreased α-smooth muscle actin (α-SMA) expression and increased podocin and synaptopodin expression. Mechanistically, Bre inhibited HG-induced nuclear factorkappaB (NF-κB) signalling activation and subsequently decreased NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in a decrease in pyroptosis. Pharmacological inhibition of NLRP3 decreased HG-induced podocyte injury, whereas the NLRP3 agonist abrogated the effects of Bre on inhibiting podocyte injury. In summary, these results demonstrate that Bre alleviates HG-induced podocyte injury and improves renal function in diabetic mice, at least in part by inhibiting NF-κB/NLRP3-mediated pyroptosis.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Huan Song,Guo-Qiang Liang,Man-Shu Yu,Yun Shan,Jun Shi,Chun-Bo Jiang,Dao-Lei Ni,Mei-Xiao Sheng
Ethnopharmacological relevance Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, it is one of the most common causes of kidney disease and can lead to end-stage kidney disease, however, its pathogenesis is still complicated. The Shen-yan-yi-hao oral solution (SOLI) is an effective prescription for the clinical treatment of IgAN while its specific mechanism remains to be further elucidated. Aim of the study This study investigates SOLI's effects on IgAN in rats, particularly on the intestinal mucosal barrier, and identifies potential therapeutic targets through network pharmacology and molecular docking, validated experimentally. Materials and methods Target genes for SOLI in IgAN were identified and analysed through molecular docking and KEGG pathway enrichment. An IgAN rat model examined SOLI's effect on renal biomarkers and cytokines involved in specific pathways, ileum mucosal lesions, and the intestinal immune system. The IL-17 pathway's role was studied in IEC-6 cells with SOLI in vitro. Result Rats developed increased proteinuria and kidney damage marked by IgA deposition and inflammation. SOLI treatment significantly ameliorated these symptoms, reduced galactose-deficient Ig A1 (Gd-IgA1), and decreased cytokines like IL-17, TNF-α, IL-6 and IL-1β etc. SOLI also normalized intestinal tight junction protein expression, ameliorated intestinal damage, and regulated intestinal immune response (focused on IL-17/NF-κB signal pathway). SOLI moderated the abnormally activated IL-17 pathway, which damages intestinal epithelial cells, suggesting IgAN treatment potential. Conclusion SOLI reduces proteinuria and enhances intestinal mucosal function in IgAN rats, kidney protection in the IgAN rat model may initiate from modulating the intestinal IL-17/NF-κB pathway and subsequent Gd-IgA1 accumulation.
研究领域:
药理学
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免疫学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2022
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IF 5.572
Hui Chen,Lixing Cao,Kai Han,Han Zhang,Jinling Cui,Xuan Ma,Shuang Zhao,Chong Zhao,Shutao Yin,Lihong Fan,Hongbo Hu
Patulin (PAT) is a common food-borne mycotoxin with diverse toxic effects including nephrotoxicity . The induction of oxidative stress is suggested to be a key mechanism contributed to toxicities of PAT. Reduced glutathione (GSH), a sulfhydryl-containing tripeptide , is a key reason for PAT-mediated oxidative stress. Cystine/glutamate antiporter (system x c − )-mediated cystine uptake plays a critical role in maintaining redox balance via promoting GSH biosynthesis. In this study, we addressed if GSH reduction by PAT was associated with inhibition of system x c − -mediated GSH biosynthesis. Results showed that PAT significantly decreased activity of SLC7A11, a core subunit of system x c − , through activating AMPK-mediated formation of beclin1-SLC7A11 complex. Furthermore, PAT promoted ferroptosis induced by a known ferroptosis inducer RSL3 in normal renal cells, and exacerbated folic acid-induced nephrotoxicity in a mouse model of acute kidney injury . The findings of the present study provide new insights into PAT-induced kidney toxicity, and implicate that patients with ferroptosis-associated diseases maybe more susceptible to PAT.
研究领域:
毒理学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2023
·
IF 14
Cai Feng,Zongling Xiong,Xianting Sun,Hao Zhou,Tianming Wang,Ying Wang,Harrison X. Bai,Peng Lei,Weihua Liao
It is a challenging task to develop a contrast agent that not only provides excellent image contrast but also protects impaired kidneys from oxidative-related stress during angiography. Clinically approved iodinated CT contrast media are associated with potential renal toxicity, making it necessary to develop a renoprotective contrast agent. Here, we develop a CeO 2 nanoparticles (NPs)-mediated three-in-one renoprotective imaging strategy, namely, i) renal clearable CeO 2 NPs serve as a one-stone-two-birds antioxidative contrast agent, ii) low contrast media dose, and iii) spectral CT, for in vivo CT angiography (CTA). Benefiting from the merits of advanced sensitivity of spectral CT and K-edge energy of Cerium (Ce, 40.4 keV), an improved image quality of in vivo CTA is successfully achieved with a 10 times reduction of contrast agent dosage. In parallel, the sizes of CeO 2 NPs and broad catalytic activities are suitable to be filtered via glomerulus thus directly alleviating the oxidative stress and the accompanying inflammatory injury of the kidney tubules. In addition, the low dosage of CeO 2 NPs reduces the hypoperfusion stress of renal tubules induced by concentrated contrast agents used in angiography. This three-in-one renoprotective imaging strategy helps prevent kidney injury from being worsened during the CTA examination.
研究领域:
医学影像
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纳米技术
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放射学
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肾病学
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材料科学
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产品关联
DOI
PubMed
高影响因子
Urological Science
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2019
·Vol. 30
·期 5
·206
·
IF 0
Upadhyay Jyoti,Tiwari Nidhi,Rana Mahendra,Bisht Satpal S.
Background: Pesticide exposure has the potential for causing acute or chronic health effects at certain developmental stages of life. It can result in irreversible damage to structure and function of an organ. The exposure of females to pesticides before or after pregnancy is a matter of concern because of the possibility of having a child born with congenital disorders and developmental defects. Prenatal exposure of any toxicants can program the developing foetus to develop diseases that manifest in later life. Very few reports are available related to the pesticide exposure induced morphological changes in kidney which has prompted us to undertake this research study. Aim: The aim of this study is to evaluate the effect of pesticide, chlorpyrifos on the kidney development of rat neonates after being exposed prenatally to pesticides throughout their gestational period. Materials and Methods: Virgin female wistar rats weighing 200-250 gms were mated with adult males. It consisted of twelve, divided into two sub groups six rats per each were treated with selected pesticides, chlorpyrifos (insecticide) readily available commercially for various agricultural and non-agricultural settings. Insecticide chlorpyrifos was given at a dose of 10mg/kg per orally to the female rats throughout their gestation period. After gestation period rat neonates were sacrificed and their kidney section was processed for histopathological analysis. The SEM study of chlorpyrifos exposed kidney section of rat neonates was performed, investigating changes in morphometric and ultra-structural features of kidney in rat neonates. Results: The histopathological analysis shows morphological changes in the kidneys of prenatally pesticides exposed rat neonates markedly different from control group. Chlorpyrifos exposed neonates kidney shows damaged kidney corpuscles and glomeruli. Conclusion: This study concluded that pesticide exposure during gestation period to pregnant rats causes significant renal toxicity in their neonates.
研究领域:
毒理学
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发育生物学
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肾脏病学
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环境健康
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生殖毒理学
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分子病理学
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DOI
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Reziwanguli Wusiman,Shayila Haimiti,Hanikezi Abuduaini,Miaoyan Yang,Yitian Wang,Meijun Gu,Ali Sailike,Lei Gao
Renal fibrosis is a prominent feature of diabetic nephropathy (DN), and the connection between renal fibrosis and abnormal glycolysis is not fully understood. SUMO-activating enzyme subunit 1 (SAE1) plays a crucial role in the SUMO modification process and is related to abnormal glycolysis. Despite this, the specific role of SAE1 in DN and its mechanism are not well defined. To investigate this, a streptozotocin-induced diabetic CD1 mice model was used, with SAE1 suppression achieved through systemic administration of SAE1 siRNA. In parallel, human renal proximal tubular tubule HK2 cells transfected with siSAE1 were exposed to high glucose for in vitro studies. The study revealed that SAE1 levels were elevated in diabetic kidney, and the deletion of SAE1 mitigated renal fibrosis in DN mice. Such suppression in SAE1 was associated with the lower expression of hypoxia inducible factor-1α (HIF-1α) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), these alterations subsequently improved abnormal glycolysis and mesenchymal transformations in vivo and in vitro . Further experiments discovered that SAE1 stabilized transcription factor HIF-1α expression through SUMOylation, promoting PFKFB3 transcription, which enhanced glycolysis characterized by increased PFK1 activity and lactate production. Additionally, pharmacological inhibition of PFKFB3 reduced renal fibrosis in DN mice, while overexpression of PFKFB3 partly restored the glycolysis and mesenchymal transformations inhibited by SAE1 knockdown in vitro . These data demonstrate that SAE1 promotes abnormal glycolysis by HIF-1α/PFKFB3 which is responsible for the fibrotic phenotype of diabetic kidney. Inhibition of SAE1 could be an alternative strategy in combating diabetes associated-kidney fibrosis via improving aberrant glycolysis.
研究领域:
肾病学
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分子生物学
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糖尿病学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
·
IF 4.2
Yongmei Li,Fengxin Zheng,Shiqi Zhong,Kunlu Zhao,Hui Liao,Jiacheng Liang,Qiang Zheng,Huicong Wu,Shifan Zhang,Ying Cao,Ting Wu,Jianxin Pang
Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro . Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC 50 value of 7.37 ± 0.66 μM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.
研究领域:
肾病学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
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2019
·
IF 3.448
Zhaopeng Yan,Bin Zang,Xiaoying Gong,Jiangyue Ren,Rui Wang
Aims Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. Main methods Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. Key findings MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. Significance MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.
研究领域:
分子生物学
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病理学
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药理学
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DOI
PubMed
高影响因子
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