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author:("Zhao, buying")
1.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
2.  Altered Expression Profile of Renal α1D-Adrenergic Receptor in Diabetes and Its Modulation by PPAR Agonists 
Journal of Diabetes Research  2014;2014:725634.
Alpha1D-adrenergic receptor (α1D-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile of α1D-AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosiglitazone for 8–10 weeks. Gene microarray, real-time PCR, and confocal immunofluorescence microscopy were performed to assess mRNA and protein expression of α1D-AR in rat kidney tissue. Using microarray, we found that α1D-AR gene was dramatically upregulated in 22-week-old ZD rats compared to ZL controls. Quantitative PCR analysis verified a 16-fold increase in α1D-AR mRNA in renal cortex from ZD animals compared to normal controls. Chronic treatment with fenofibrate or rosiglitazone reduced renal cortical α1D-AR gene. Immunofluorescence staining confirmed that α1D-AR protein was induced in the glomeruli and tubules of diabetic rats. Moreover, dual immunostaining for α1D-AR and kidney injury molecule-1 indicated that α1D-AR was expressed in dedifferentiated proximal tubules of diabetic Zucker rats. Taken together, our results show that α1D-AR expression is upregulated in the diabetic kidneys. PPAR activation suppressed renal expression of α1D-AR in diabetic nephropathy.
doi:10.1155/2014/725634
PMCID: PMC3977090  PMID: 24772448
3.  Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia 
Hosgood, H. Dean | Wang, Wen-Chang | Hong, Yun-Chul | Wang, Jiu-Cun | Chen, Kexin | Chang, I-Shou | Chen, Chien-Jen | Lu, Daru | Yin, Zhihua | Wu, Chen | Zheng, Wei | Qian, Biyun | Park, Jae Yong | Kim, Yeul Hong | Chatterjee, Nilanjan | Chen, Ying | Chang, Gee-Chen | Hsiao, Chin-Fu | Yeager, Meredith | Tsai, Ying-Huang | Wei, Hu | Kim, Young Tae | Wu, Wei | Zhao, Zhenhong | Chow, Wong-Ho | Zhu, Xiaoling | Lo, Yen-Li | Sung, Sook Whan | Chen, Kuan-Yu | Yuenger, Jeff | Kim, Joo Hyun | Huang, Liming | Chen, Ying-Hsiang | Gao, Yu-Tang | Kim, Jin Hee | Huang, Ming-Shyan | Jung, Tae Hoon | Caporaso, Neil | Zhao, Xueying | Huan, Zhang | Yu, Dianke | Kim, Chang Ho | Su, Wu-Chou | Shu, Xiao-Ou | Kim, In-San | Bassig, Bryan | Chen, Yuh-Min | Cha, Sung Ick | Tan, Wen | Chen, Hongyan | Yang, Tsung-Ying | Sung, Jae Sook | Wang, Chih-Liang | Li, Xuelian | Park, Kyong Hwa | Yu, Chong-Jen | Ryu, Jeong-Seon | Xiang, Yongbing | Hutchinson, Amy | Kim, Jun Suk | Cai, Qiuyin | Landi, Maria Teresa | Lee, Kyoung-Mu | Hung, Jen-Yu | Park, Ju-Yeon | Tucker, Margaret | Lin, Chien-Chung | Ren, Yangwu | Perng, Reury-Perng | Chen, Chih-Yi | Jin, Li | Chen, Kun-Chieh | Li, Yao-Jen | Chiu, Yu-Fang | Tsai, Fang-Yu | Yang, Pan-Chyr | Fraumeni, Joseph F. | Seow, Adeline | Lin, Dongxin | Zhou, Baosen | Chanock, Stephen | Hsiung, Chao Agnes | Rothman, Nathaniel | Lan, Qing
Human genetics  2012;131(7):10.1007/s00439-012-1144-8.
A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10−12); however, this association did not achieve genome-wide significance (p < 10−7) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10−8; allelic risk = 0.80, 95% confidence interval (CI) = 0.74–0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67–0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
doi:10.1007/s00439-012-1144-8
PMCID: PMC3875137  PMID: 22367405
4.  Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer 
The Oncologist  2012;17(12):1551-1561.
Thirteen tag SNPs at the CASP8 and CASP10 loci in patients with advanced NSCLC were genotyped in a two-stage analysis consisting of a discovery set and an independent validation set. These SNPs were evaluated for their association with toxicity outcomes with platinum-based chemotherapy.
Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens.
doi:10.1634/theoncologist.2011-0419
PMCID: PMC3528388  PMID: 22843554
CASP8; CASP10; Polymorphisms; Platinum-based chemotherapy; Toxicity; Non-small cell lung cancer; Association
5.  USP4 Positively Regulates RIG-I-Mediated Antiviral Response through Deubiquitination and Stabilization of RIG-I 
Journal of Virology  2013;87(8):4507-4515.
Protein ubiquitination plays an essential role in the regulation of retinoic acid-inducible gene I (RIG-I) activation and the antiviral immune response. However, the function of the opposite process of deubiquitination in RIG-I activation remains elusive. In this study, we have identified the deubiquitinating enzyme ubiquitin-specific protease 4 (USP4) as a new regulator for RIG-I activation through deubiquitination and stabilization of RIG-I. USP4 expression was attenuated after virus-induced RIG-I activation. Overexpression of USP4 significantly enhanced RIG-I protein expression and RIG-I-triggered beta interferon (IFN-β) signaling and, at the same time, inhibited vesicular stomatitis virus (VSV) replication. Small interfering RNA (siRNA) knockdown of USP4 expression had an opposite effect. Furthermore, USP4 was found to interact with RIG-I and remove K48-linked polyubiquitination chains from RIG-I. Therefore, we identified USP4 as a new positive regulator for RIG-I that acts through deubiquitinating K48-linked ubiquitin chains and stabilizing RIG-I.
doi:10.1128/JVI.00031-13
PMCID: PMC3624380  PMID: 23388719
6.  Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Purpose
Genetic variation may influence chemotherapy response and overall survival in cancer patients.
Experimental design
We conducted a genome-wide scan in 535 advanced-stage non–small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA).
Results
Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10−5 to 4.19 × 10−7 in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population.
Conclusion
In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients.
doi:10.1158/1078-0432.CCR-12-1202
PMCID: PMC3723686  PMID: 22872573
7.  TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1 
The Journal of Experimental Medicine  2012;209(10):1703-1711.
TRAF-interacting protein (TRIP) negatively regulates TLR3/4- and RIG-I–induced IFN-β signaling by promoting K48-linked ubiquitination and proteasomal degradation of TBK1.
TANK-binding kinase 1 (TBK1) plays an essential role in Toll-like receptor (TLR)– and retinoic acid–inducible gene I (RIG-I)–mediated induction of type I interferon (IFN; IFN-α/β) and host antiviral responses. How TBK1 activity is negatively regulated remains largely unknown. We report that TNF receptor-associated factor (TRAF)–interacting protein (TRIP) promotes proteasomal degradation of TBK1 and inhibits TLR3/4- and RIG-I–induced IFN-β signaling. TRIP knockdown resulted in augmented activation of IFN regulatory factor 3 (IRF3) and enhanced expression of IFN-β in TLR3/4- and RIG-I–activated primary peritoneal macrophages, whereas overexpression of TRIP had opposite effects. Consistently, TRIP impaired Sendai virus (SeV) infection–induced IRF3 activation and IFN-β production and promoted vesicular stomatitis virus (VSV) replication. As an E3 ubiquitin ligase, TRIP negatively regulated the cellular levels of TBK1 by directly binding to and promoting K48-linked polyubiquitination of TBK1. Therefore, we identified TRIP as a negative regulator in TLR3/4- and RIG-I–triggered antiviral responses and suggested TRIP as a potential target for the intervention of diseases with uncontrolled IFN-β production.
doi:10.1084/jem.20120024
PMCID: PMC3457734  PMID: 22945920
8.  Genome-Wide Association Study Identifies a Novel Susceptibility Locus at 12q23.1 for Lung Squamous Cell Carcinoma in Han Chinese 
PLoS Genetics  2013;9(1):e1003190.
Adenocarcinoma (AC) and squamous cell carcinoma (SqCC) are two major histological subtypes of lung cancer. Genome-wide association studies (GWAS) have made considerable advances in the understanding of lung cancer susceptibility. Obvious heterogeneity has been observed between different histological subtypes of lung cancer, but genetic determinants in specific to lung SqCC have not been systematically investigated. Here, we performed the GWAS analysis specifically for lung SqCC in 833 SqCC cases and 3,094 controls followed by a two-stage replication in additional 2,223 lung SqCC cases and 6,409 controls from Chinese populations. We found that rs12296850 in SLC17A8-NR1H4 gene region at12q23.1 was significantly associated with risk of lung SqCC at genome-wide significance level [additive model: odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.72–0.84, P = 1.19×10−10]. Subjects carrying AG or GG genotype had a 26% (OR = 0.74, 95% CI = 0.67–0.81) or 32% (OR = 0.68, 95% CI = 0.56–0.83) decreased risk of lung SqCC, respectively, as compared with AA genotype. However, we did not observe significant association between rs12296850 and risk of lung AC in a total of 4,368 cases with lung AC and 9,486 controls (OR = 0.96, 95% CI = 0.90–1.02, P = 0.173). These results indicate that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese population.
Author Summary
Previous genome-wide association studies (GWAS) strongly suggested the importance of genetic susceptibility for lung cancer. However, the studies specific to different histological subtypes of lung cancer were limited. We performed the GWAS analysis specifically for lung squamous cell carcinoma (SqCC) with 570,009 autosomal SNPs in 833 SqCC cases and 3,094 controls and replicated in additional 2,223 lung SqCC cases and 6,409 controls from Chinese populations (822 SqCC cases and 2,243 controls for the first replication stage and 1,401 SqCC cases and 4,166 controls for the second replication stage). We found a novel association at rs12296850 (SLC17A8-NR1H4) on12q23.1. However, rs12296850 didn't show significant association with risk of lung adenocacinoma (AC) in 4,368 lung AC cases and 9,486 controls. These results indicate that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese population.
doi:10.1371/journal.pgen.1003190
PMCID: PMC3547794  PMID: 23341777
9.  Prediction of lung cancer risk in a Chinese population using a multifactorial genetic model 
BMC Medical Genetics  2012;13:118.
Background
Lung cancer is a complex polygenic disease. Although recent genome-wide association (GWA) studies have identified multiple susceptibility loci for lung cancer, most of these variants have not been validated in a Chinese population. In this study, we investigated whether a genetic risk score combining multiple.
Methods
Five single-nucleotide polymorphisms (SNPs) identified in previous GWA or large cohort studies were genotyped in 5068 Chinese case–control subjects. The genetic risk score (GRS) based on these SNPs was estimated by two approaches: a simple risk alleles count (cGRS) and a weighted (wGRS) method. The area under the receiver operating characteristic (ROC) curve (AUC) in combination with the bootstrap resampling method was used to assess the predictive performance of the genetic risk score for lung cancer.
Results
Four independent SNPs (rs2736100, rs402710, rs4488809 and rs4083914), were found to be associated with a risk of lung cancer. The wGRS based on these four SNPs was a better predictor than cGRS. Using a liability threshold model, we estimated that these four SNPs accounted for only 4.02% of genetic variance in lung cancer. Smoking history contributed significantly to lung cancer (P < 0.001) risk [AUC = 0.619 (0.603-0.634)], and incorporated with wGRS gave an AUC value of 0.639 (0.621-0.652) after adjustment for over-fitting. This model shows promise for assessing lung cancer risk in a Chinese population.
Conclusion
Our results indicate that although genetic variants related to lung cancer only added moderate discriminatory accuracy, it still improved the predictive ability of the assessment model in Chinese population.
doi:10.1186/1471-2350-13-118
PMCID: PMC3573944  PMID: 23228068
Chinese; Cumulative risk; Genetic risk score; Lung cancer; Risk assessment
10.  Glomerular Expression of Kidney Injury Molecule-1 and Podocytopenia in Diabetic Glomerulopathy 
American Journal of Nephrology  2011;34(3):268-280.
Background/Aims
Studies have shown that kidney injury molecule-1 (KIM-1) is upregulated in damaged renal proximal tubules. In this study, we examined KIM-1 expression in glomerular epithelial cells in diabetic glomerulopathy.
Methods
Renal histology, immunostaining and Western blot for protein level, and real-time PCR for mRNA expression of KIM-1 and podocyte markers were evaluated in untreated or losartan-treated Zucker lean (Fa/+) and Zucker diabetic fatty (Fa/Fa) rats.
Results
The diabetic rats showed an increased glomerular expression of KIM-1. KIM-1 staining was localized primarily in the hyperplastic parietal epithelium of Bowman's capsule in the early stages of diabetes with subsequent increase in KIM-1-positive cells in the glomerular tuft in the more advanced stages. The increase in glomerular KIM-1 was associated with a decrease in podocytes in Fa/Fa rats. Antiproteinuric treatment with losartan attenuated podocytopenia and decreased renal expression of KIM-1 in treated diabetic rats. In an in vitro study, albumin overload increased KIM-1 protein in the primary cultures of rat glomerular epithelial cells.
Conclusion
These results show that glomerular KIM-1 expression was increased, in proportion to the extent of proteinuria and podocytopenia in the diabetic animals, supporting that KIM-1 could be used as a potential biomarker for glomerular injury in proteinuric kidney disease.
doi:10.1159/000330187
PMCID: PMC3169370  PMID: 21822010
Albuminuria; Kidney injury molecule-1; Parietal epithelial cells; Podocytes; Glomerulopathy
11.  Effect of Polymorphisms in XPD on Clinical Outcomes of Platinum-Based Chemotherapy for Chinese Non-Small Cell Lung Cancer Patients 
PLoS ONE  2012;7(3):e33200.
Purpose
Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
Experimental Design
353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg156Arg, Asp312Asn, Asp711Asp and Lys751Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing.
Results
Variant genotypes of XPD Asp312Asn, Asp711Asp and Lys751Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp312Asn, Asp711Asp and Lys751Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10−4, log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0–1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS.
Conclusions
Our study provides evidence for the predictive role of XPD Asp312Asn, Asp711Asp and Lys751Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.
doi:10.1371/journal.pone.0033200
PMCID: PMC3315552  PMID: 22479369
12.  Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-κB and transforming growth factor-β1/Smad3 in diabetic nephropathy 
Fibrates, the ligands of peroxisome proliferator-activated receptor-α, have been shown to have a renal protective action in diabetic models of renal disease, but the mechanisms underlying this effect are unknown. In the present study, we sought to investigate in greater detail the effect of fenofibrate and its mechanism of action on renal inflammation and tubulointerstitial fibrosis in an animal model of type 2 diabetes mellitus. Twelve-week-old non-diabetic Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with vehicle or fenofibrate for 10 weeks. mRNA and protein analyses were performed by real-time polymerase chain reaction, Western blot and immunostaining. The diabetic condition of ZD rats was associated with an increase in collagen and α-smooth muscle actin accumulation in the kidney, which was significantly reduced by fenofibrate. Chronic treatment of ZD rats with fenofibrate attenuated renal inflammation and tubular injury as evidenced by a decrease in mRNA and protein expression of secreted phosphoprotein-1, monocyte chemotactic protein-1 and kidney injury molecule-1 in the kidneys. Renal interstitial macrophage infiltration was also significantly reduced in the kidneys of fenofibrate-treated diabetic animals. Moreover, renal nuclear factor (NF)-κB DNA-binding activity, transforming growth factor (TGF)-β1 and phospho-Smad3 proteins were significantly higher in ZD animals compared with ZL ones. This increase in NF-κB activity, TGF-β1 expression and Smad3 phosphorylation was greatly attenuated by fenofibrate in the diabetic kidneys. Taken together, fenofibrate suppressed NF-κB and TGF-β1/Smad3 signaling pathways and reduced renal inflammation and tubulointerstitial fibrosis in diabetic ZD animals.
doi:10.1258/ebm.2009.009218
PMCID: PMC3057137  PMID: 20404057
inflammation; kidney; peroxisome proliferator-activated receptor-α; renal injury; type 2 diabetes
13.  Increased Renal Proximal Convoluted Tubule Transport Contributes to Hypertension in Cyp4a14 Knockout Mice 
Nephron. Physiology  2009;113(4):p23-p28.
Background/Aims
Disrupting the enzyme Cyp4a14 in mice leads to hypertension, which is more severe in the male mice and appears to be due to androgen excess. Because the Cyp4a14 enzyme is located in the proximal tubule of the kidney, we hypothesized that there could be dysregulation of transport in this segment that could contribute to the hypertension.
Methods
Wild-type (SV/129) mice and mice that had targeted disruption of the Cyp4a14 gene were studied. Proximal convoluted tubules (PCT) from knockout and wild-type mice were dissected and perfused in vitrofor measurement of volume absorption (JV). Expression of the sodium-hydrogen exchanger 3 (NHE3), the predominant transporter responsible for sodium transport in this segment, was measured by immunoblot. Renal vascular (afferent arteriole) responses to angiotensin and endothelin were also measured.
Results
PCT volume absorption was elevated in tubules from the Cyp4a14 knockout mice as compared to the wild-type mice. Brush border membrane NHE3 expression was almost 2-fold higher in Cyp4a14 knockout mice than in wild-type mice. No difference was found in the afferent arteriolar response.
Conclusion
Thus, hypertension in the Cyp4a14 knockout mice appears to be driven by excessive fluid reabsorption in the proximal tubule, which is secondary to overexpression of NHE3.
doi:10.1159/000235774
PMCID: PMC2790762  PMID: 19713718
In vitro microperfusion; Proximal tubule transport; Eicosanoids
14.  An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension 
Hypertension  2005;46(4):975-981.
The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10±2 ng/mL in normal-salt angiotensin hypertension and 19±3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161±4 mm Hg in normal-salt and 172±5 mmHg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140±5 mm Hg in the normal-salt angiotensin hypertension group and to 151±6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension.
doi:10.1161/01.HYP.0000176237.74820.75
PMCID: PMC1444888  PMID: 16157792
kidney; inflammation; endothelium-derived factors; albuminuria

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