Small
·
2022
·Vol. 18
·期 48
·2204388
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IF 15.153
Jiajia Li,Qijia Duan,Xiaona Wei,Jianping Wu,Qiongqiong Yang
Acute kidney injury (AKI) is a common clinical disease with high morbidity and mortality, and with a lack of effective drugs for treatment. Oxidative stress is very important in the occurrence and progression of AKI, and antioxidants use is one of the promising treatments. Rosmarinic acid (RA) is a ubiquitous natural polyphenol with powerful antioxidant and anti-inflammatory activities. Due to its inherent characteristic with poor water solubility and inferior bioavailability, its clinical application is impeded. Hence, the authors design a nanoparticle for effectively delivering RA, which is a chemical complex of RA and fourth-generation poly-amidoamine-based amphiphilic polymer (G4-PAMAM). The nanoparticle is modified with l-serine due to the specific interaction between kidney injury molecule–1 (Kim-1) and serine, which eventually generates a promising AKI kidney–targeting nanoparticle (S-G-R). The S-G-R is rapidly cumulated and long-term retained in ischemia-reperfusion–induced AKI kidneys, especially in the damaged renal tubular cells. The S-G-R exhibits more excellent antioxidative and antiapoptotic effects in vitro and has a more outstanding ability to improve the renal function, repair damaged renal tissue, and decrease oxidative stress, inflammatory response and apoptosis of tubular cells in vivo. Overall, this study might develop a safe and effective targeting strategy for the therapy of AKI.
研究领域:
药学
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纳米技术
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肾脏生理学
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药理学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Mingrui Xiong,Hong Chen,Yu Fan,Muchuan Jin,Dong Yang,Yuchen Chen,Yu Zhang,Robert B. Petersen,Hua Su,Anlin Peng,Congyi Wang,Ling Zheng,Kun Huang
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout ( Apela Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
研究领域:
肾病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2020
·
IF 2.971
Xuemei Liu,Deliang Liu,Youyou Shuai,Huilin Li,Hengxia Zhao,Xin Qu,Shufang Chu,Xuewen Zhang
Context HuoxueJiangtang decoction (ZY) is a traditional Chinese medicine for the treatment of diabetes.Objective The protective effect of ZY on renal injury in diabetic nephropathy rats was investigated in this study.Materials and methods Fifty 4-week-old SPF Wistar male rats were selected to construct diabetic nephropathy model rats (DN) group by continuous high-fat feeding for 4 weeks, followed by a tail vein injection of 30 mg/kg streptozotocin for 1 week. The experimental rats were divided into six groups of 10 rats: normal (control), DN, DN + ZY, DN + metformin, DN + metformin + ZY, and DN + metformin + captopril (positive control) groups. Among the groups, 6.25 g/kg ZY, 250 mg/kg metformin, and 17.5 mg/kg captopril were given to the rats by gavage once a day for 16 weeks. Blood glucose, dietary behaviour, biochemical indicators, and gene expression changes were measured in each group.Results Metformin + ZY treatment significantly lowered blood glucose, water intake, urine total protein, urine albumin, urine volume, serum triglyceride, and serum cholesterol levels in the DN group. The pathological changes of kidney tissue showed that the DN + metformin + ZY group had a protective effect on kidney tissue damage. And ZY and metformin + ZY treatments repaired the expression of genes in the DN group.Discussion and conclusion The ZY and metformin combined treatment showed a clear therapeutic effect on kidney damage in DN. This study provides a potential mechanism for the treatment of diabetic nephropathy with ZY combined with metformin.
研究领域:
中医药学
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糖尿病研究
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肾脏病学
✓ 已验证
DOI
高影响因子
JCI Insight
·
2025
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IF 6.1
Ping Gao,Xinwei Cheng,Maochang Liu,Hui Peng,Guodong Li,Tianze Shang,Jianqiao Wang,Qianyan Gao,Chenglong Zhu,Zhenpeng Qiu,Chengliang Zhang
Tacrolimus-induced chronic nephrotoxicity (TICN) hinders its long-term use, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate NFAT. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in various homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain- and loss-of-function rescued the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation both by phosphorylation sites mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-seq data. Growth arrest and DNA damage-inducible 45α (GADD45α) was identified as a transcriptional target of TFEB via chromatin immunoprecipitation and dual luciferase reporter assays. And then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro, and vise versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of TFEB-GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention of TICN.
研究领域:
药理学
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肾病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2022
·
IF 14.224
Lirong Huang,Kun Jia,Haibin Xiong,Guiyou Tian,Jiaxin Xu,Wei Yuan,Chen Lu,Xiaoping Xiao,Huiqiang Lu
Nephrotoxicity of oxyfluorfen to vertebrates remains unclear despite its wide use as a herbicide. In order to further study its nephrotoxicity and its underlying mechanism, we used human embryonic kidney cells and zebrafish to explore. HEK293T cells were exposed to 2, 4, 6 μg/mL oxyfluorfen for 24 h in vitro, and zebrafish were exposed to 0.4, 0.8, 1.2 mg/L oxyfluorfen for 72 h in vivo. We found that oxyfluorfen inhibits cell migration and induces oxidative stress and apoptosis, causing kidney damage or nephrotoxicity in embryonic and adult zebrafish. Oxyfluorfen triggered inflammation in zebrafish and causing severe periorbital and body edema in embryos. Oxyfluorfen induced the secretion of kidney injury markers, including urea nitrogen (BUN), creatinine (CR), and β-n-acetyl-glucosaminidase (NAG) in zebrafish. Additionally, oxyfluorfen affected the homeostasis of oxidant and antioxidant systems, leading to reactive oxygen species (ROS) overload. Oxyfluorfen also damaged the glomerular podocytes and induced apoptosis of proximal tubules, which is harmful to normal body function and the renal filtration system. These results indicate that oxyfluorfen is a potential environmental hazard that can cause severe kidney injury and affect the health of organisms.
研究领域:
毒理学
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环境科学
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细胞生物学
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动物学
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产品关联
DOI
高影响因子
Open Medicine
·
2023
·Vol. 18
·期 1
·
IF 2.1
Huaibin Sun,Zhiguo Peng,Kao Liu,Shengli Liu
Norepinephrine (NE) has a certain effect on the improvement of renal function. However, whether NE can alleviate cyclosporin A (CsA)-induced nephrotoxicity needs further study. The effect of CsA (1.25, 2.5, 5, and 10 μM) on the human renal epithelial cell vitality, lactate dehydrogenase (LDH) activity, apoptosis, and secreted frizzled-related protein 1 (SFRP1) level was examined by cell counting kit-8, enzyme-linked immunosorbent assay, flow cytometer, and western blot. The effect of NE on the LDH activity, apoptosis, and SFRP1 level of human renal epithelial cells induced by CsA was examined again. After silencing of SFRP1 in human renal epithelial cells, the SFRP1 level, cell vitality, and apoptosis were examined again. CsA (1.25, 2.5, 5, and 10 μM) attenuated the cell vitality and SFRP1 level but enhanced the LDH activity and apoptosis in human renal epithelial cells, while the above effects were reversed by NE. Moreover, SFRP1 silencing reversed the regulation of NE on the SFRP1 level, cell vitality, and apoptosis in human renal epithelial cells induced by CsA. In conclusion, NE relieved CsA-induced nephrotoxicity via enhancing the expression of SFRP1.
Graphical abstract
研究领域:
药理学
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肾病学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Fujing Wang,Rong Hu,Jiaxing Zhang,Tingting Pei,Zhuo'en He,Liliang Ju,Zhongxiao Han,Mingqing Wang,Wei Xiao
Renal fibrosis is the pathological consequence of progressive chronic kidney disease . Although it has been reported that vitamin D3 exerts antifibrotic effects, the underlying mechanisms remain unclear. This study is aimed at investigating the effects and molecular mechanisms in high-dose vitamin D3 treatment on renal fibrosis. A model of chronic kidney disease was established by 5/6 nephrectomy in rats characterised by high levels of serum creatine, urea nitrogen, and urinary protein. Serum 25-dihydroxyvitamin D3, calcium and parathormone levels were measured to evaluate vitamin D levels. Hematoxylin and eosin , periodic acid Schiff and Mallory's Trichrome staining were used to evaluate histopathological changes in rats. Moreover, the expression of vimentin , collagen I, α-smooth muscle actin and E-cadherin were analyzed at molecular and histopathological levels. Our results showed that exposure to vitamin D3 decreased the levels of serum creatine, urea nitrogen and urine protein and restored the homeostasis of calcium and parathormone. Vitamin D3 also downregulated the expression of vimentin, collagen I and α-smooth muscle actin and attenuated renal fibrosis and epithelial to mesenchymal transition in the kidney. Importantly, vitamin D3 treatment increased the expression of the vitamin D receptor and inhibited Transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway in rats kidneys with chronic kidney disease. Mechanistically, the upregulation of TGF-β1 and phosphorylation of Smad3 induced by vitamin D3 was reversed by activation of the vitamin D receptor. Our findings indicated that vitamin D3 is a potential antifibrotic drug in chronic kidney disease via the vitmin D receptor and inhibiting TGF-β1/Smad3 signaling pathway.
研究领域:
肾病学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NUCLEAR MEDICINE AND BIOLOGY
·
2022
·
IF 2.947
Hongliang Wang,Liu Yang,Keyi Lu,Xiaoshan Guo,Rui Xi,Weixuan Dong,Kaixin Qin,Haiyan Liu,Hua Wei,Yan Cheng,Zhifang Wu,Sijin Li
Objective Given the limitation of biomarkers to predict the renal function progression in diabetic nephropathy , N-(6-[ 18 F]Fluoropyridin-3-yl)glycine (6-[ 18 F]FPyGly) was used to evaluate renal function progression in a rat model of diabetic nephropathy. Methods Twenty male Sprague-Dawley rats were randomly divided into four groups, including the healthy control group (HC group), diabetic nephropathy group (DNM group), routine diet treated diabetic nephropathy group (RDNM group), and high fat/high sucrose -diet-fed diabetic nephropathy group (HDNM group). All renal function parameters were determined from animal PET renograms . P and T max represent the curve peak counts and the time to the curve peak counts of 6-[ 18 F]FPyGly in kidneys after injection, C 1/2 and the 15 min/Peak ratio represent the time from peak to 1/2 peak in the clearance phase, and the ratio of the curve counts at 15 min to the curve peak counts. Results P, T max , C 1/2 , and 15 min/peak ratio of each rat were significantly correlated with S-Cr, BUN . There were significant differences in T max , P, serum creatinine (S Cr), and blood urea nitrogen (BUN) levels between HC and DNM groups. P and the 15 min/Peak ratio were significantly different among DNM, RDNM, and HDNM groups, while T max and C 1/2 were only significantly different between DNM and RDNM or HDNM groups. There only was a significant difference in BUN between the DNM and HDNM groups. Conclusion The renal function parameters P, T max , C 1/2 and 15 min/peak value obtained by dynamic renal imaging based on 6-[ 18 F]FPyGly could reflect changes of renal function in rats, which had a good correlation with S Cr and BUN, and showed more efficient in the diagnosis of diabetic nephropathy and renal function classification than S Cr and BUN.
研究领域:
医学影像
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核医学
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糖尿病
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肾脏生理
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Xiaowei Zhang,Liang Zhao,Shixie Xiang,Yiran Sun,Pan Wang,Jenny Jie Chen,Brian Sheng-Xian Teo,Zhishen Xie,Zhenqiang Zhang,Jiangyan Xu
Ethnopharmacological relevance Yishen Tongluo formula (YSTLF) is formulated based on traditional Chinese medicine theory for the treatment of Diabetic kidney disease (DKD) and has been shown to be effective in improving the symptoms of DKD according to the clinical observation. Aim of the study To explore the effect of YSTLF on DKD and figure out whether its effects were due to the regulation Sirt6/TGF-β1/Smad2/3 pathway and promoting degradation of TGF-β1. Materials and methods The extract of YSTLF at 1, 2.5 and 5 g/kg was orally administered to C57BLKS/J ( db/db ) mice for 8 weeks and db/db mice were given valsartan as a positive control. The littermate db/m and db/db mice were given vehicle as the control and model group, respectively. Blood urea nitrogen and serum creatinine were detected and the urinary albumin excretion, urea albumin creatinine ratio was calculated. The histopathological change of renal tissues in each group was determined. Simultaneously, the levels of fibrosis-related proteins and messenger RNA (mRNA) in kidney and high glucose (HG)-induced SV40-MES-13 cells were detected. The roles of YSTLF in regulating of Sirt6/TGF-β1/Smad2/3 signaling pathway were investigated in HG-stimulated SV40-MES-13 cells and validated in db/db mice. Furthermore, the effect of YSTLF on TGF-β1 degradation was investigated in HG-stimulated SV40-MES-13 cells. Results YSTLF significantly improved the renal function in DKD mice. YSTLF dose-dependently attenuated pathological changes and suppressed the expression of type I collagen , alpha smooth muscle actin , type IV collagen , and fibronectin in vitro and in vivo , resulting in ameliorating of renal fibrosis . YSTLF positively regulated Sirt6 expression, while inhibited the activating of TGF-β1/Smad2/3 signaling pathway. TGF-β1 was steady expressed in HG-stimulated SV40-MES-13 cells, whereas was continuously degraded under YSTLF treatment. Conclusions YSTLF significantly ameliorates renal damages and fibrosis may via regulating Sirt6/TGF-β1/Smad2/3 signaling pathway as well as promoting the degradation of TGF-β1.
研究领域:
药理学
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内分泌学
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分子生物学
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中医
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
·
IF 3.3
Miao Xing,Xiaoyu Ma,Xi Wang,Haoze Wang,Minjuan Xie,Ziwen Zhang,Jie Zhou
Emodin has been demonstrated to possess multiple pharmacological activities. However, emodin has also been reported to induce nephrotoxicity at high doses and with long-term use, and the underlying mechanism has not been fully disclosed. The current study aimed to investigate the roles of oxidative stress and ferroptosis in emodin-induced kidney toxicity. Mice were intraperitoneally treated with emodin, and NRK-52E cells were exposed to emodin in the presence or absence of treatment with Jagged1, SC79, or t-BHQ. Emodin significantly upregulated the levels of blood urea nitrogen, serum creatinine, malondialdehyde, and Fe 2+ , reduced the levels of superoxide dismutase and glutathione, and induced pathological changes in the kidneys in vivo. Moreover, the viability of NRK-52E cells treated with emodin was reduced, and emodin induced iron accumulation, excessive reactive oxygen species production, and lipid peroxidation and depolarized the mitochondrial membrane potential ( ΔΨm ). In addition, emodin treatment downregulated the activity of neurogenic locus notch homolog protein 1 (Notch1), reduced the nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2), and decreased glutathione peroxidase 4 protein levels. However, Notch1 activation by Jagged1 pretreatment, Akt activation by SC79 pretreatment, or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of emodin in NRK-52E cells. Taken together, these results revealed that emodin-induced ferroptosis triggered kidney toxicity through inhibition of the Notch1/Nrf2/glutathione peroxidase 4 axis.
研究领域:
药理学
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毒理学
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细胞生物学
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肾脏生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zou Meina,Chen Yanrong,Zheng Zongji,Sheng Shuyue,Jia Yijie,Wang Xiangyu,Ren Shijing,Yang Yanling,Li Xiaomin,Dong Wenhui,Guan Meiping,Zhang Qian,Xue Yaoming
High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.
研究领域:
肾病学
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内分泌学
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药理学
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代谢学
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-14
·
IF 16.6
Liu Di,Song Yanling,Chen Hui,You Yuchan,Zhu Luwen,Zhang Jucong,Xu Xinyi,Hu Jiahao,Huang Xiajie,Wu Xiaochuan,Xu Xiaoling,Jiang Saiping,Du Yongzhong
Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′) 2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′) 2 ) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′) 2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′) 2 -SS31, comprising the anti-VEGFR2 F(ab′) 2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′) 2 . These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
研究领域:
药理学
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肾病学
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糖尿病
✓ 已验证
DOI
PubMed
高影响因子
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