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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(6): 987-996, 2023 Dec 30.
Article in Chinese | MEDLINE | ID: mdl-38173112

ABSTRACT

As the incidence of diabetes mellitus is rapidly increasing worldwide,that of related complications,such as diabetic kidney disease(DKD),also increases,conferring a heavy economic burden on the patients,families,society,and government.Diabetes mellitus complicated with chronic kidney disease(CKD)includes DKD and the CKD caused by other reasons.Because of the insufficient knowledge about CKD,the assessment of diabetes mellitus complicated with CKD remains to be improved.The therapies for diabetes mellitus complicated with CKD focus on reducing the risk factors.In clinical practice,DKD may not be the CKD caused by diabetes.According to clinical criteria,some non-diabetic kidney disease may be misdiagnosed as DKD and not be treated accurately.This review summarizes the status quo and research progress in the assessment,diagnosis,and treatment of diabetes mellitus complicated with CKD and predicts the directions of future research in this field.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetes Mellitus , Diabetic Nephropathies , Renal Insufficiency, Chronic , Humans , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/therapy , Diabetic Nephropathies/etiology , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/therapy , Risk Factors , Diabetes Mellitus/diagnosis , Diabetes Mellitus/therapy
2.
BMC Infect Dis ; 22(1): 125, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-35123391

ABSTRACT

BACKGROUND: Schistosomiasis is one of the most contagious parasitic diseases affecting humans; however, glomerular injury is a rare complication mainly described with Schistosoma mansoni infection. We report a case of membranous nephropathy associated with Schistosoma japonicum infection in a Chinese man. CASE PRESENTATION: A 51-year-old Chinese male with a long history of S. japonicum infection presented to the hospital with a slowly progressing severe lower limb edema and foaming urine for over 5 months. Serum S. japonicumantigen test was positive and immunohistochemistry showed that the glomeruli were positive for the antigens. The renal pathologic diagnosis was stage III membranous nephropathy. The patient was treated with glucocorticoid, praziquantel, and an angiotensin-converting enzyme inhibitor. The edema in both lower limbs disappeared within 2 weeks, but his renal function declined progressively and proteinuria persisted after 5 months of therapy. CONCLUSIONS: Different classes of schistosomal glomerulopathy have completely different clinical manifestation and prognosis. Therefore, efforts should focus on alleviating symptoms, prevention, and early detection. S. japonicumassociated with membranous nephropathy may show a good curative effect and prognosis. However, it is necessary to monitor the renal function in such patients.


Subject(s)
Glomerulonephritis, Membranous , Schistosoma japonicum , Schistosomiasis japonica , Schistosomiasis mansoni , Schistosomiasis , Animals , Glomerulonephritis, Membranous/complications , Glomerulonephritis, Membranous/diagnosis , Glomerulonephritis, Membranous/drug therapy , Humans , Kidney , Male , Middle Aged , Schistosomiasis japonica/complications , Schistosomiasis japonica/diagnosis , Schistosomiasis japonica/drug therapy
3.
Chin Med J (Engl) ; 132(23): 2872-2880, 2019 Dec 05.
Article in English | MEDLINE | ID: mdl-31856060

ABSTRACT

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.


Subject(s)
Fibrosis/metabolism , Fibrosis/pathology , Hydrogen Sulfide/metabolism , Kidney/pathology , Animals , Disease Progression , Humans
5.
Kidney Blood Press Res ; 40(1): 89-99, 2015.
Article in English | MEDLINE | ID: mdl-26029782

ABSTRACT

BACKGROUND/AIMS: We evaluated the therapeutic effects of fluorofenidone (AKF-PD), a novel pyridone agent, targeting oxidative stress and fibrosis in obstructive nephropathy. METHODS: AKF-PD was used to treat renal interstitial fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of NOX2 (gp91phox), fibronectin and extracellular signal regulated kinase (ERK) were detected by western blot. A level of Malondialdehyde (MDA), an oxidative stress marker, was measured by ELISA. In addition, ROS and the expressions of NOX2, collagen I (a1), fibronectin and p-ERK were measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial cells (NRK-52E) in culture. RESULTS: In NRK-52E cells, AKF-PD reduced AngII induced expressions of ROS, NOX2, fibronectin, collagen I (a1) and p-ERK. In UUO kidney cortex, AKF-PD attenuated the degree of renal interstitial fibrosis, which was associated with reduced the expressions of collagen I (a1) and fibronectin. Furthermore, AKF-PD downregulated the expressions of NOX2, MDA and p-ERK. CONCLUSION: AKF-PD treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK/MAPK signaling pathway.


Subject(s)
Kidney Diseases/drug therapy , Kidney Diseases/enzymology , MAP Kinase Signaling System/drug effects , Membrane Glycoproteins/antagonists & inhibitors , NADPH Oxidases/antagonists & inhibitors , Oxidative Stress/drug effects , Pyridones/therapeutic use , Animals , Fibrosis , Gene Expression Regulation, Enzymologic , Kidney Diseases/pathology , MAP Kinase Signaling System/physiology , Male , Membrane Glycoproteins/biosynthesis , NADPH Oxidase 2 , NADPH Oxidases/biosynthesis , Oxidative Stress/physiology , Pyridones/pharmacology , Rats , Rats, Sprague-Dawley
6.
Mol Cell Biochem ; 407(1-2): 77-87, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26033204

ABSTRACT

Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.


Subject(s)
Kidney Diseases/enzymology , Kidney Diseases/prevention & control , Pyridones/administration & dosage , STAT3 Transcription Factor/metabolism , Animals , Cell Line , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/genetics , Disease Models, Animal , Gene Expression Regulation , Kidney Diseases/genetics , Male , Mesangial Cells/drug effects , Mesangial Cells/metabolism , Mice , Phosphorylation/drug effects , Pyridones/pharmacology , Rats , Rats, Sprague-Dawley , STAT3 Transcription Factor/genetics
7.
Pharmazie ; 69(9): 680-4, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25272939

ABSTRACT

OBJECTIVES: IL-1beta is a potent proinflammatory, pro-fibrogenetic and pro-athrosclerosis cytokine which has been shown to play an important role in an expanding number of noninfectious, chronic inflammatory conditions including cardiovascular disease, renal fibrosis, rheumatoid arthritis and even type 2 diabetes. Losartan is an angiotensin II receptor antagonist widely used for the treatment of hypertension, diabetic nephropathy and congestive heart failure. In this study, we attempted to clarify whether losartan has an inhibitory effect on IL-1beta. To further elucidate the molecular mechanism underlying the anti-IL-1beta property of losartan, we studied the LPS+ATP-induced activation of NALP3 inflammasome which controls the muturation and secretion of IL-1beta. METHODS: LPS and ATP were used to stimulate the release of IL-1beta from thioglycollate-elicited macrophages from BALB/c mice. The production of IL-1beta was evaluated by ELISA assay and NALP3, caspase-1, IL-beta mRNA levels were determined by reverse transcription-polymerase chain reaction. RESULTS: In cultured thioglycollate-elicited macrophages, we observed that LPS + ATP greatly enhanced IL-1 beta secretion (6938.00 +/- 83.45; P < 0.05) and the mRNA levels of NALP3, caspase-1 which are two main components of NALP3 inflammasome (60.88 +/- 8.28; 1.31 +/- 0.04, P < 0.05 for both). The macrophages co-cultured with losartan showed low production of IL-1beta (3907.50 +/- 143.61; P < 0.05) and low production of NALP3, caspase-1mRNA (29.82 +/- 6.92; 1.12 +/- 0.05, P < 0.05 for both). Losartan did not reduce IL-1beta mRNA(P > 0.05). CONCLUSIONS: Our results show that the NALP3 inflammasome is up-regulated and activated in the mouse macrophage in response to LPS + ATP stimulation. Losartan is able to suppress the LPS + ATP-induced production of IL-1beta protein. In addition, this effectmay be partially mediated by suppressing NALP3 inflammasome activation.


Subject(s)
Adenosine Triphosphate/antagonists & inhibitors , Adenosine Triphosphate/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/immunology , Interleukin-1beta/metabolism , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Losartan/pharmacology , Macrophages/metabolism , Animals , Carrier Proteins/biosynthesis , Caspase 1/biosynthesis , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Enzyme-Linked Immunosorbent Assay , Immunity, Cellular/drug effects , Macrophages/drug effects , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Male , Mice , Mice, Inbred BALB C , NLR Family, Pyrin Domain-Containing 3 Protein , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction
8.
Nephrology (Carlton) ; 18(10): 690-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23841831

ABSTRACT

AIM: Oxidative stress plays an important role in the progression of renal interstitial fibrosis. The nicotinamide adeninedinucleotide phosphate (NADPH) oxidase (Nox) family is considered one of the major sources of reactive oxygen species (ROS). In the present study, we investigated the inhibitory effects of a novel anti-fibrotic agent, Fluorofenidone (AKF-PD), upon Nox-mediated oxidative stress and deposition of extracellular matrix (ECM) in the development of renalinterstitial fibrosis. METHODS: AKF-PD was used to treat renal fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of Nox homologues, p-Akt, collagen I and III were detected by immunoblotting or immunohistochemistry. Levels of 8-iso prostaglandin F2alpha (8-Iso PGF2a) was measured by enzyme linked immunosorbent assay. In addition, ROS and the expression of collagen I (1a), Nox subunits and p-Akt was measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial (NRK-52E) cells in culture. RESULTS: AKF-PD treatment significantly attenuated tubulo-interstitial injury, ECM deposition and oxidative stress in fibrotic rat kidneys. In addition, AKF-PD inhibited the expression of ROS, Collagen I (1a), Nox2, p-Akt in Ang II-stimulated NRK-52E cells. CONCLUSION: AKF-PD attenuates the progression of renal interstitial fibrosis partly by suppressing NADPH oxidase and ECM deposition via the PI3K/Akt signalling pathway, suggesting AKF-PD is a potential novel therapeutic agent against renal fibrosis.


Subject(s)
Antioxidants/pharmacology , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Enzyme Inhibitors/pharmacology , Kidney Diseases/prevention & control , Kidney Tubules/drug effects , NADPH Oxidases/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Pyridones/pharmacology , Signal Transduction/drug effects , Angiotensin II/pharmacology , Animals , Cell Line , Class Ia Phosphatidylinositol 3-Kinase/genetics , Collagen Type I/metabolism , Dinoprost/analogs & derivatives , Dinoprost/metabolism , Disease Models, Animal , Fibrosis , Kidney Diseases/enzymology , Kidney Diseases/etiology , Kidney Diseases/pathology , Kidney Tubules/enzymology , Kidney Tubules/pathology , Lipid Peroxidation/drug effects , Losartan/pharmacology , Male , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/metabolism , NADPH Oxidase 2 , NADPH Oxidases/metabolism , Oxidative Stress/drug effects , Phosphorylation , Rats , Rats, Sprague-Dawley , Transfection , Ureteral Obstruction/complications
9.
Pharmacology ; 88(1-2): 88-99, 2011.
Article in English | MEDLINE | ID: mdl-21847000

ABSTRACT

BACKGROUND/AIMS: Fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD], a novel pyridone agent, showed potent antifibrotic properties. The aim of the present study was to investigate the effects of AKF-PD on diabetic nephropathy and kidney fibrosis, and to obtain an insight into its mechanisms of action. METHODS: We administered AKF-PD to diabetic db/db mice for 12 weeks. Moreover, we performed in vitro cultures using murine mesangial cells exposed to high ambient glucose concentrations. RESULTS: AKF-PD reduced renal hypertrophy, mesangial matrix expansion and albuminuria in the db/db mice. The upregulated expression of α1(I)- and α1(IV)-collagen and fibronectin mRNAs, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase 1 (TIMP-1) mRNAs and proteins was inhibited by AKF-PD treatment in the renal cortex of db/db mice. The maximal effective dose of AKF-PD was about 500 mg/kg body weight. AKF-PD inhibited the upregulated expression of α1(I)- and α1(IV)-collagens, TGF-ß1, TIMP-1 and α-SMA induced by high glucose concentrations in cultured mesangial cells. CONCLUSIONS: Our data indicate that AKF-PD diminishes the abnormal accumulation of mesangial matrix through the inhibition of upregulated expression of TGF-ß target genes in kidneys of db/db mice, resulting in attenuation of renal fibrosis and amelioration of renal dysfunction despite persistent hyperglycemia. Therefore, AKF-PD, a potent antifibrotic agent, holds great promise in the treatment of diabetic nephropathy.


Subject(s)
Diabetic Nephropathies/drug therapy , Hypoglycemic Agents/pharmacology , Kidney Diseases/drug therapy , Kidney/physiopathology , Pyridones/pharmacology , Albumins/analysis , Animals , Blood Glucose , Cell Culture Techniques , Collagen/physiology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/physiopathology , Disease Models, Animal , Drug Evaluation, Preclinical , Extracellular Matrix/metabolism , Fibronectins/physiology , Fibrosis/pathology , Fibrosis/physiopathology , Hyperglycemia/drug therapy , Hyperglycemia/metabolism , Hyperglycemia/pathology , Hyperglycemia/physiopathology , Hypoglycemic Agents/therapeutic use , Kidney/pathology , Kidney Cortex/physiopathology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Male , Mice , Mice, Knockout , Pyridones/therapeutic use , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/physiology
10.
Mol Cell Biochem ; 354(1-2): 263-73, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21594754

ABSTRACT

Fluorofenidone (FD) is a novel pyridone agent with significant antifibrotic effects in vitro. The purpose of this study is to investigate the effects of FD on renal interstitial fibrosis in rats with obstructive nephropathy caused by unilateral ureteral obstruction (UUO). With pirfenidone (PD, 500 mg/kg/day) and enalapril (10 mg/kg/day) as the positive treatment controls, the rats in different experimental groups were administered with FD (500 mg/kg/day) from day 4 to day 14 after UUO. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and type III collagen, transforming growth factor-ß(1) (TGF-ß(1)), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), α-smooth muscle actin (α-SMA), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed. FD treatment significantly attenuated the prominently increased scores of tubulointerstitial injury, interstitial collagen deposition, and protein expression of type I and type III collagen in ureter-obstructed kidneys, respectively. As compared with untreated rats, FD also significantly reduced the expression of α-SMA, TGF-ß(1), CTGF, PDGF, and inhibitor of TIMP-1 in the obstructed kidneys. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy through its regulation on fibrogenic growth factors, tubular cell transdifferentiation, and extracellular matrix.


Subject(s)
Kidney Diseases/drug therapy , Kidney Tubules/pathology , Pyridones/pharmacology , Ureteral Obstruction/complications , Actins/metabolism , Animals , Collagen Type I/metabolism , Collagen Type III/metabolism , Connective Tissue Growth Factor/genetics , Connective Tissue Growth Factor/metabolism , Drug Evaluation, Preclinical , Fibrosis , Kidney Diseases/etiology , Kidney Diseases/pathology , Kidney Tubules/metabolism , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Platelet-Derived Growth Factor/genetics , Platelet-Derived Growth Factor/metabolism , Pyridones/therapeutic use , Rats , Rats, Sprague-Dawley , Tissue Inhibitor of Metalloproteinase-1/genetics , Tissue Inhibitor of Metalloproteinase-1/metabolism , Transcription, Genetic , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism
11.
Int Immunopharmacol ; 11(9): 1327-32, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21586345

ABSTRACT

OBJECTIVES: The present study was designed to investigate the inhibitory effects of fluorofenidone on Ang II-induced apoptosis in renal tubular cells and the related signaling pathway. METHODS: Rat proximal tubular epithelial cells (NRK-52E) were used to examine the anti-apoptosis effects of fluorofenidone. Cell proliferation was assessed by methyl thiazolyl tetrazolium assay. Apoptosis was examined by AO/EB staining and TUNEL assay. The expression of Fas/FasL pathway members, including Fas, FasL, Bax, Bcl-2, Caspase-8, and Caspase-3 was detected by real-time RT-PCR and/or Western blot, respectively. The activity of Caspase-8 and Caspase-3 was detected by spectrophotometry. RESULTS: Fluorofenidone didn't affect the proliferation of NRK-52E cells, but significantly inhibited the apoptosis of NRK-52E cells induced by Ang II. Fluorofenidone significantly reduced Ang II-induced increases in Fas, FasL, Bax, Caspase-8 and Caspase-3 at the mRNA level. Consistent with these observations, fluorofenidone also prevented Ang II-mediated up-regulation of FasL and Bax at the protein level. Additionally, Ang II-induced activation of Caspase-8 and Caspase-3 as well as Ang II-initiated downregulation of Bcl-2 at both mRNA and protein levels was all prevented by fluorofenidone. CONCLUSIONS: Fluorofenidone can inhibit Ang II-induced apoptosis of renal tubular cells through blockage of the Fas/FasL pathway.


Subject(s)
Angiotensin II/antagonists & inhibitors , Apoptosis/drug effects , Fas Ligand Protein/antagonists & inhibitors , Kidney Tubules, Proximal/drug effects , Pyridones/pharmacology , fas Receptor/antagonists & inhibitors , Angiotensin II/metabolism , Animals , Caspase 3/genetics , Caspase 3/metabolism , Caspase 8/genetics , Caspase 8/metabolism , Caspase Inhibitors , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Down-Regulation , Fas Ligand Protein/genetics , Fas Ligand Protein/metabolism , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Signal Transduction/drug effects , Up-Regulation , bcl-2-Associated X Protein/antagonists & inhibitors , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism , fas Receptor/genetics , fas Receptor/metabolism
12.
Pharmazie ; 64(10): 680-4, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19947172

ABSTRACT

OBJECTIVES: The development of novel antifibrotic agent candidates for the treatment of diabetic nephropathy. The present study was designed to investigate the potential mechanism of fluorofenidone involving the downregulation of CTGF expression induced by TGF-beta1 and the related signaling pathway in mouse mesangial cells (MMCs). METHODS: Mouse mesangial cells were applied to explore the involvement of MAPK in TGF-beta1 signal pathway to CTGF, and the regulation of fluorofenidone. The activation of three major members of MAPK, including ERK1/2, P38 and JNK was detected by Western blot; the expression of CTGF was investigated by real time PCR and Western blot. RESULTS: Fluorofenidone significantly reduced the phosphorylation of ERK1/2, P38 and JNK induced by TGF-beta1. Fluorofenidone, PD98059 and SB203580 could partially inhibit TGF-beta1-induced expression of CTGF in mouse mesangial cells, however, JNK inhibitor II had no effect. CONCLUSIONS: The antifibrotic effects of fluorofenidone are suggested to be mediated byits actions through inhibition of MAPK activation and consequent reduction of CTGF expression.


Subject(s)
Connective Tissue Growth Factor/biosynthesis , Connective Tissue Growth Factor/genetics , Fibrinolytic Agents/pharmacology , Mesangial Cells/metabolism , Mitogen-Activated Protein Kinases/physiology , Pyridones/pharmacology , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/pharmacology , Animals , Blotting, Western , Down-Regulation/drug effects , Mesangial Cells/drug effects , Mice , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
13.
Nephrology (Carlton) ; 14(6): 565-72, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19712256

ABSTRACT

AIM: Fluorofenidone (1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone) is a novel pyridone agent. The aim of the present study is to investigate the effects of fluorofenidone on angiotensin (Ang)II-induced fibrosis and the involved molecular mechanism in rat proximal tubular epithelial cells. METHODS: NRK-52E cells, a rat proximal tubular epithelial cell line, were incubated with medium containing AngII, with or without nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI), losartan, fluorofenidone (2, 4 and 8 mmol/L) and pirfenidone (8 mmol/L) for 24 h. Cells in the serum-free medium were controls. The expression of three subunits of NADPH oxidase, including p47phox, Nox-4 and p22phox, were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and western blot. NADPH oxidase activity was measured directly by superoxide dismutase (SOD) inhibitable cytochrome C reduction assay. The generation of reactive oxygen species (ROS) was measured by dichlorofluorescein fluorescence analysis. The mRNA and protein expression of collagen I and transforming growth factor (TGF)-beta1 were determined by real-time RT-PCR and enzyme-linked immunosorbent assay. RESULTS: Fluorofenidone significantly inhibited TGF-beta1 and collagen I expression upregulation induced by AngII or TGF-beta1 respectively. Moreover, fluorofenidone greatly reduced the elevation of expression and activity of NADPH oxidase and inhibited ROS generation induced by AngII in rat proximal tubular epithelial cells. These responses were also attenuated by DPI, losartan, and pirfenidone. CONCLUSION: Fluorofenidone acted as an anti-oxidative and anti-fibrotic agent through the mechanisms of blocking NADPH oxidase-dependent oxidative stress and inhibiting TGF-beta1 expression in rat proximal tubular epithelial cells.


Subject(s)
Collagen Type I/antagonists & inhibitors , Fibrosis/drug therapy , NADPH Oxidases/physiology , Pyridones/pharmacology , Transforming Growth Factor beta1/antagonists & inhibitors , Animals , Cells, Cultured , Collagen Type I/genetics , Kidney/pathology , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , NADPH Oxidases/genetics , Rats , Superoxides/metabolism , Transforming Growth Factor beta1/genetics
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 25(6): 486-9, 2009 Jun.
Article in Chinese | MEDLINE | ID: mdl-19500499

ABSTRACT

AIM: To investigate the effects and mechanism of losartan on expression of CTGF induced by high glucose. METHODS: Mouse mesangial cells (MMCs) were cultured in vitro, initially, MMCs were stimulated by high glucose(25 mmol/L glucose) for 24 h, 48 h, 72 h, the phosphorylation of ERK1/2 was assessed by Western blot. Then MMCs were randomly divided into 5 groups: (1) Low glucose group (5.6 mmol/L glucose); (2)Sorbitol group (5.6 mmol/L glucose + 19.4 mmol/L sorbitol); (3) High glucose group (25 mmol/L glucose); (4) Losartan group (25 mmol/L glucose + 10(5) mol/L losartan); (5) ERK inhibitors group (25 mmol/L glucose + 25 micromol/L PD98059). After 48 hours, the phosphorylation of ERK1/2 were detected by Western blot. After 72 hours, the protein and mRNA expression level of CTGF were assessed by Western blot and real-time PCR. RESULTS: High glucose induced the phosphorylation of ERK1/2 in a time-dependent manner. The protein expression of phosphor-ERK1/2 and CTGF were increased in high glucose group comparing with low glucose group(P<0.01), and reduced in losartan group and ERK inhibitors group comparing with high glucose group(P<0.05). The mRNA expression of CTGF was increased in high glucose group comparing with low glucose group(P<0.01) , and reduced in losartan group and ERK inhibitors group comparing with high glucose group(P<0.01). CONCLUSION: Losartan can inhibit high glucose-induced CTGF expression in mouse mesangial cells, and the mechanisms maybe involve the interruption of ERK1/2 MAPK pathway.


Subject(s)
Connective Tissue Growth Factor/metabolism , Glucose/pharmacology , Losartan/pharmacology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Signal Transduction/drug effects , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Blotting, Western , Cells, Cultured , Connective Tissue Growth Factor/genetics , Dose-Response Relationship, Drug , Gene Expression/drug effects , Mice , Reverse Transcriptase Polymerase Chain Reaction , Time Factors
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