Name: Chris Antony Mathew Pittappillil
Student No:s3770345
RBM4002 – Bachelor of Science Honours (Biomedical Sciences) 2018
Cisplatin-induced Acute Kidney Injury, treated with AVE0991 (Mas-receptor Angiotensin II (1-7) agonist)
Supervisor:Dr. Anthony Zulli
Colleagues:Renee Smith, Tawar Qaradakhi,
Alexander Tacey, Laura Gadanec,
Rima Hamad, Kristin McSweeney
Assignment Type: Research Plan
I acknowledge the work submitted is my own and has referenced appropriately, acknowledging various authors and researchers of related topics to avoid any plagiarism.
Introduction
Acute Kidney Injury (AKI) is an abrupt decline in glomerular filtration rate (GFR), leading to tubular necrosis ADDIN EN.CITE <EndNote><Cite><Author>Qu</Author><Year>2018</Year><RecNum>250</RecNum><DisplayText>(1)</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521711707″>250</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Qu, Y.</author><author>An, F.</author><author>Luo, Y.</author><author>Lu, Y.</author><author>Liu, T.</author><author>Zhao, W.</author><author>Lin, B.</author></authors></contributors><auth-address>State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Institute of Cancer Stem Cell, Dalian Medical University, China. State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Electronic address: [email protected] Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. College of Stomatology, Dalian Medical University, Dalian, China.</auth-address><titles><title>A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title></periodical><pages>41-53</pages><volume>155</volume><edition>2017/11/24</edition><keywords><keyword>Aki</keyword><keyword>Microfluidics</keyword><keyword>Nephron</keyword><keyword>Nephrotoxicity</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1878-5905 (Electronic) 0142-9612 (Linking)</isbn><accession-num>29169037</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29169037</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2017.11.010</electronic-resource-num></record></Cite></EndNote>(1). AKI is a huge global public health concern as it impacts 13.3 million patients per year ADDIN EN.CITE <EndNote><Cite><Author>Qu</Author><Year>2018</Year><RecNum>250</RecNum><DisplayText>(1)</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521711707″>250</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Qu, Y.</author><author>An, F.</author><author>Luo, Y.</author><author>Lu, Y.</author><author>Liu, T.</author><author>Zhao, W.</author><author>Lin, B.</author></authors></contributors><auth-address>State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Institute of Cancer Stem Cell, Dalian Medical University, China. State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Electronic address: [email protected] Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. College of Stomatology, Dalian Medical University, Dalian, China.</auth-address><titles><title>A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title></periodical><pages>41-53</pages><volume>155</volume><edition>2017/11/24</edition><keywords><keyword>Aki</keyword><keyword>Microfluidics</keyword><keyword>Nephron</keyword><keyword>Nephrotoxicity</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1878-5905 (Electronic) 0142-9612 (Linking)</isbn><accession-num>29169037</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29169037</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2017.11.010</electronic-resource-num></record></Cite></EndNote>(1). 20 – 60% of critically ill patients suffer from AKI leading to high mortality of 1.7 million deaths per year ADDIN EN.CITE <EndNote><Cite><Author>Qu</Author><Year>2018</Year><RecNum>250</RecNum><DisplayText>(1)</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521711707″>250</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Qu, Y.</author><author>An, F.</author><author>Luo, Y.</author><author>Lu, Y.</author><author>Liu, T.</author><author>Zhao, W.</author><author>Lin, B.</author></authors></contributors><auth-address>State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Institute of Cancer Stem Cell, Dalian Medical University, China. State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Electronic address: [email protected] Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. College of Stomatology, Dalian Medical University, Dalian, China.</auth-address><titles><title>A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title></periodical><pages>41-53</pages><volume>155</volume><edition>2017/11/24</edition><keywords><keyword>Aki</keyword><keyword>Microfluidics</keyword><keyword>Nephron</keyword><keyword>Nephrotoxicity</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1878-5905 (Electronic) 0142-9612 (Linking)</isbn><accession-num>29169037</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29169037</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2017.11.010</electronic-resource-num></record></Cite></EndNote>(1). There is a huge burden financially as medical expenses increase each year ADDIN EN.CITE <EndNote><Cite><Author>Qu</Author><Year>2018</Year><RecNum>250</RecNum><DisplayText>(1)</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521711707″>250</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Qu, Y.</author><author>An, F.</author><author>Luo, Y.</author><author>Lu, Y.</author><author>Liu, T.</author><author>Zhao, W.</author><author>Lin, B.</author></authors></contributors><auth-address>State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Institute of Cancer Stem Cell, Dalian Medical University, China. State Key Laboratory of Fine Chemicals, Department of Chemical Engineering &amp; School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Electronic address: [email protected] Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. College of Stomatology, Dalian Medical University, Dalian, China.</auth-address><titles><title>A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title></periodical><pages>41-53</pages><volume>155</volume><edition>2017/11/24</edition><keywords><keyword>Aki</keyword><keyword>Microfluidics</keyword><keyword>Nephron</keyword><keyword>Nephrotoxicity</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1878-5905 (Electronic) 0142-9612 (Linking)</isbn><accession-num>29169037</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29169037</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2017.11.010</electronic-resource-num></record></Cite></EndNote>(1). 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ADDIN EN.CITE.DATA (1, 5). Many cancer therapies incur huge costs and the use of platinum drugs such as cisplatin increases oxidative stress, affecting renal proximal tubules PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXNhcmk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (6).

Cisplatin-induced cancer therapies are mainly used to treat sizable tumours on head, neck, ovaries, prostate and breast PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWhnaGFuaTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA (9). Renal I/R triggers an inflammatory cascade PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051
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Tm90ZT4A
ADDIN EN.CITE.DATA (9, 10).Research Plan – Overview
C57BL/6 mice model
Male
10 – 20 weeks of age
20 – 25g in weight
N (number of mice) – 52
Sourced from ARC (Australian Research Council)
After death
44450018034000Blood from carotidSpleen – Dr. Apostolopolous

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166370020320
Blood urea nitrogen (BUN)GFR
sCr (Serum Creatinine)
SMDA
838200142240Aorta Renal ArteryHeartKidney
379730010160

436880053340CHOP
Isometric test, organ bathWestern Blotting – detection
ThromboxanePCR – concentrationHSP72
Acetylcholine – dosage curvePAS– damage (necrosis)GRP78

Intraperitoneal Injection (IP)
Drug doses will be administered by IP, which are calculated from published literatures. All volumes injected will be 200?l/animal.

Cisplatin – 200L (25mg/Kg in phosphate buffer solution)
AVE0991 (drug of choice) – 1mg/Kg/day (calculated from 3mg/Kg via oral gavage) 200L
Saline – 200L of DMSO (vehicle).

On day 0, saline, which will be marked as vehicle, injected into 24 mice along with AVE0991 (drug of choice) injected into one set of 12 mice, from the above mentioned 24 mice, as the other set of 12 mice will be marked as control. On day 1, another 12 mice will be injected with saline and cisplatin drug. On day 2, another 12 mice will be injected with cisplatin and AVE0991 drugs along with saline. On day 3, all mice will be euthanised.

Aim: Identifying the effects of novel drug AVE0991 on cisplatin-induced acute kidney injury
Hypothesis: AVE0991 promotes vasodilation by increasing the NO production, decreasing inflammation and oxidative stress.

Materials:
Cisplatin, NAC and apocynin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Lactacte dehydrogenase (LDH), 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT), Reactive Oxygen Species Assay Kit (ROS) and Annexin V-FITC/PI Apoptosis Detection Kit was obtained from Beyotime (Shanghai, China). Periodic acid Schiff (PAS), Creatinine Assay Kit, BUN Assay Kit and Malondialdehyde (MDA) Assay Kit were purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China).

Blood Measurement
After mice are euthanised, blood samples will be collected to measure BUN (blood urea and nitrogen – waste products) & sCr (serum creatine – protein) – measuring GFR (glomerular filtration rate). If serum creatine, blood urea and nitrogen levels are high it could be an indicator of a decrease in GFR , which can illustrate renal failure or AKI. This is measured using Creatinine and BUN assay kit.

Serum MDA levels will be measured using – Malondialdehyde (MDA) assay kit, in order to determine biomarkers for oxidative stress within the kidney epithelial cells caused by an increase in reactive oxygen species (ROS) – Oxygen superoxide (O2-) and hydrogen peroxide (H2O2), which decreases the production of antioxidants – superoxide dismutase (SOD) and glutathione (GSH) ADDIN EN.CITE <EndNote><Cite><Author>Meng</Author><Year>2018</Year><RecNum>296</RecNum><DisplayText>(10)</DisplayText><record><rec-number>296</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521773040″>296</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Meng, X. M.</author><author>Ren, G. L.</author><author>Gao, L.</author><author>Yang, Q.</author><author>Li, H. D.</author><author>Wu, W. F.</author><author>Huang, C.</author><author>Zhang, L.</author><author>Lv, X. W.</author><author>Li, J.</author></authors></contributors><auth-address>School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. Anhui Institute of Innovative Drugs, Hefei, Anhui, China. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China. Huainan First People&apos;s Hospital and First Affiliated Hospital of Anhui University of Science &amp; Technology, Huainan, Anhui, China.</auth-address><titles><title>NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation</title><secondary-title>Lab Invest</secondary-title></titles><periodical><full-title>Lab Invest</full-title></periodical><pages>63-78</pages><volume>98</volume><number>1</number><edition>2017/11/07</edition><dates><year>2018</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1530-0307 (Electronic) 0023-6837 (Linking)</isbn><accession-num>29106395</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29106395</url></related-urls></urls><electronic-resource-num>10.1038/labinvest.2017.120</electronic-resource-num></record></Cite></EndNote>(10).

LDH assay
Kidney cells will be seeded in 96-well plates and treated in the presence or absence of 20L cisplatin for 24-hour after incubation with apocynin overnight. A portion will be removed from each well as the maximum enzyme activity control wells added to LDH release reagent. After an hour, 96-well plates, centrifuge for 5 mins with a centrifuge of 400g. Subsequently 120L supernatant of each well will be added to new 96-well plates. Cells are then incubated with 60L LDH detection working solution, then placed in the dark for 30 minutes at room temperature. The Optical Density (OD) will be measured with microplate reader at 490nM wavelength. This allows to measure cytotoxicity (toxic contents) within kidney cells. Cytotoxicity of each group is calculated as following: ADDIN EN.CITE <EndNote><Cite><Author>Dickhout.</Author><Year>2016</Year><RecNum>372</RecNum><DisplayText>(12)</DisplayText><record><rec-number>372</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524105064″>372</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>J G Dickhout.</author><author>J Chahal.</author><author>A Matthews.</author><author>R E Carlisle.</author><author>V Tat.</author><author>Naiel Safaa</author></authors></contributors><titles><title>Endoplasmic Reticulum Stress Causes Renal Epithelial Cell Disjunction</title><secondary-title>Journal of Pharmacology Reports</secondary-title></titles><periodical><full-title>Journal of Pharmacology Reports</full-title></periodical><pages>1-5</pages><volume>1</volume><number>1</number><edition>8 February 2016</edition><section>1</section><keywords><keyword>Endoplasmic reticulum stress</keyword><keyword>Epithelial junctions</keyword><keyword>?-catenin</keyword><keyword>Acute kidney injury</keyword></keywords><dates><year>2016</year><pub-dates><date>5 February 2016</date></pub-dates></dates><work-type>Journal Article</work-type><urls></urls><language>English</language></record></Cite></EndNote>(12)
%cell death = (LDH release experiment – LDH concentration medium)
(LDH release cell lysis – LDH concentration medium)
Determining ROS Production
The production of ROS will be measured using florescent dye 2′,7′-dichlorofluorescein diacetate (DCFHDA). DCFH is converted to a highly fluorescent 2′,7′-dichlorofluorescein, while ROS is present and are detected by fluorescence microscopy. Cells will then be seeded into six-well culture plates and incubated with 20M cisplatin in the presence or absence of NOX-inhibitor apocynin. This test will help to identify the reactive oxygen species – oxygen superoxide (O2-) and hydrogen peroxide (H2O2) in kidney cells; found to decrease nitric oxide (NO) production causing AKI ADDIN EN.CITE <EndNote><Cite><Author>Meng</Author><Year>2018</Year><RecNum>296</RecNum><DisplayText>(10)</DisplayText><record><rec-number>296</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521773040″>296</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Meng, X. M.</author><author>Ren, G. L.</author><author>Gao, L.</author><author>Yang, Q.</author><author>Li, H. D.</author><author>Wu, W. F.</author><author>Huang, C.</author><author>Zhang, L.</author><author>Lv, X. W.</author><author>Li, J.</author></authors></contributors><auth-address>School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. Anhui Institute of Innovative Drugs, Hefei, Anhui, China. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China. Huainan First People&apos;s Hospital and First Affiliated Hospital of Anhui University of Science &amp; Technology, Huainan, Anhui, China.</auth-address><titles><title>NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation</title><secondary-title>Lab Invest</secondary-title></titles><periodical><full-title>Lab Invest</full-title></periodical><pages>63-78</pages><volume>98</volume><number>1</number><edition>2017/11/07</edition><dates><year>2018</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1530-0307 (Electronic) 0023-6837 (Linking)</isbn><accession-num>29106395</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29106395</url></related-urls></urls><electronic-resource-num>10.1038/labinvest.2017.120</electronic-resource-num></record></Cite></EndNote>(10). Cells will be treated in subsequent operations according to the instructions.

Western Blotting
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ADDIN EN.CITE.DATA (13, 16).

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ADDIN EN.CITE.DATA (17). It is also an immunoglobulin heavy chain binding protein, localised in the ER PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaXU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (21). The HSP subfamily is composed of four isomers HSC70-inducible isoform, HSP72, mHSP75 and GRP78 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJyZXJhLUNoaW1hbDwvQXV0aG9yPjxZZWFyPjIwMTE8
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ADDIN EN.CITE.DATA (21). HSP72 is expressed in response to cellular stress and its induction can be as great as 15% of the total protein PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJyZXJhLUNoaW1hbDwvQXV0aG9yPjxZZWFyPjIwMTE8
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ADDIN EN.CITE.DATA (21). Given that HSP72 is induced in renal tubules during AKI and that proximal detachment is projected to the urinary space; reasoning that urinary HSP72 levels can serve as a possible early biomarker to detect, monitor or stratify AKI PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJyZXJhLUNoaW1hbDwvQXV0aG9yPjxZZWFyPjIwMTE8
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ADDIN EN.CITE.DATA (21).
Membranes are blocked with 5% milk for 2hours – to break non-specific binding, then incubated with the primary antibody against KIM-1 molecule, -actin, NOX2, NOX4, RIPK3, Phosphor-MLKL ADDIN EN.CITE <EndNote><Cite><Author>Han</Author><Year>2002</Year><RecNum>302</RecNum><DisplayText>(22)</DisplayText><record><rec-number>302</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521846414″>302</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Han, W. K.</author><author>Bailly, V.</author><author>Abichandani, R.</author><author>Thadhani, R.</author><author>Bonventre, J. V.</author></authors></contributors><auth-address>Medical Services, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.</auth-address><titles><title>Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury</title><secondary-title>Kidney Int</secondary-title></titles><periodical><full-title>Kidney Int</full-title></periodical><pages>237-44</pages><volume>62</volume><number>1</number><edition>2002/06/26</edition><keywords><keyword>Acute Kidney Injury/diagnosis/urine</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Biomarkers</keyword><keyword>Cell Adhesion Molecules/*urine</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Kidney Tubular Necrosis, Acute/urine</keyword><keyword>Kidney Tubules, Proximal/*pathology</keyword><keyword>Male</keyword><keyword>*Membrane Proteins</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2002</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0085-2538 (Print) 0085-2538 (Linking)</isbn><accession-num>12081583</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12081583</url></related-urls></urls><electronic-resource-num>10.1046/j.1523-1755.2002.00433.x</electronic-resource-num></record></Cite></EndNote>(22) and cleaved caspase 3 overnight at 4C. Followed by incubation with secondary antibody (detects first antibody) at room temperature for 2-hours. Signals will be recorded using LICOR/Odyssey infrared image system. The intensities of each western blotting band will be quantified and analysed. This test will help to analyse the dysfunctional protein bands while injury is present in the kidney. Proteins (CHOP, GRP78 and HSP72) from mouse kidney tissue, will be extracted with RIPA lysis buffer, and concentration of protein by BCA protein assay kit.

PCR
Total RNA extracted from mouse kidney tissues will be analysed by TRI-ZOL (Invitrogen) according to the manufacturer’s instruction. -actin, KIM-1, TNF- and IL-1 ADDIN EN.CITE ;EndNote;;Cite;;Author;Meng;/Author;;Year;2018;/Year;;RecNum;296;/RecNum;;DisplayText;(10);/DisplayText;;record;;rec-number;296;/rec-number;;foreign-keys;;key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521773040″;296;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Meng, X. M.;/author;;author;Ren, G. L.;/author;;author;Gao, L.;/author;;author;Yang, Q.;/author;;author;Li, H. D.;/author;;author;Wu, W. F.;/author;;author;Huang, C.;/author;;author;Zhang, L.;/author;;author;Lv, X. W.;/author;;author;Li, J.;/author;;/authors;;/contributors;;auth-address;School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. Anhui Institute of Innovative Drugs, Hefei, Anhui, China. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China. Huainan First People;apos;s Hospital and First Affiliated Hospital of Anhui University of Science ;amp; Technology, Huainan, Anhui, China.;/auth-address;;titles;;title;NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation;/title;;secondary-title;Lab Invest;/secondary-title;;/titles;;periodical;;full-title;Lab Invest;/full-title;;/periodical;;pages;63-78;/pages;;volume;98;/volume;;number;1;/number;;edition;2017/11/07;/edition;;dates;;year;2018;/year;;pub-dates;;date;Jan;/date;;/pub-dates;;/dates;;isbn;1530-0307 (Electronic) 0023-6837 (Linking);/isbn;;accession-num;29106395;/accession-num;;urls;;related-urls;;url;https://www.ncbi.nlm.nih.gov/pubmed/29106395;/url;;/related-urls;;/urls;;electronic-resource-num;10.1038/labinvest.2017.120;/electronic-resource-num;;/record;;/Cite;;/EndNote;(10) will be used as sequence of primers. Ratio for mRNA of interest index – will be normalised to -actin and will be expressed as mean SEM ADDIN EN.CITE ;EndNote;;Cite;;Author;Meng;/Author;;Year;2018;/Year;;RecNum;296;/RecNum;;DisplayText;(10);/DisplayText;;record;;rec-number;296;/rec-number;;foreign-keys;;key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521773040″;296;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Meng, X. M.;/author;;author;Ren, G. L.;/author;;author;Gao, L.;/author;;author;Yang, Q.;/author;;author;Li, H. D.;/author;;author;Wu, W. F.;/author;;author;Huang, C.;/author;;author;Zhang, L.;/author;;author;Lv, X. W.;/author;;author;Li, J.;/author;;/authors;;/contributors;;auth-address;School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. Anhui Institute of Innovative Drugs, Hefei, Anhui, China. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China. Huainan First People;apos;s Hospital and First Affiliated Hospital of Anhui University of Science ;amp; Technology, Huainan, Anhui, China.;/auth-address;;titles;;title;NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation;/title;;secondary-title;Lab Invest;/secondary-title;;/titles;;periodical;;full-title;Lab Invest;/full-title;;/periodical;;pages;63-78;/pages;;volume;98;/volume;;number;1;/number;;edition;2017/11/07;/edition;;dates;;year;2018;/year;;pub-dates;;date;Jan;/date;;/pub-dates;;/dates;;isbn;1530-0307 (Electronic) 0023-6837 (Linking);/isbn;;accession-num;29106395;/accession-num;;urls;;related-urls;;url;https://www.ncbi.nlm.nih.gov/pubmed/29106395;/url;;/related-urls;;/urls;;electronic-resource-num;10.1038/labinvest.2017.120;/electronic-resource-num;;/record;;/Cite;;/EndNote;(10). This test will show the molecular changes in kidney tissue damage.

Immunofluorescence
Kidney tissues will be cultured in eight-chamber glass slides in the presence or absence of 20M cisplatin for 24hours after incubation with apocynin overnight. Tissue sample fixed in 2% paraformaldehyde and incubated with primary antibodies against KIM-1 and TNF- at 4C overnight followed by incubation with secondary antibodies (anti-rabbit IgG rhodamine) for 1hour. Tissues are then counterstained (detects nucleus) with DAPI and analysed using fluorescence microscope. The number of positive cells from the randomised nucleated cells, will be expressed as percentage of positive cell score ADDIN EN.CITE ;EndNote;;Cite;;Author;Bonavia;/Author;;Year;2017;/Year;;RecNum;288;/RecNum;;DisplayText;(23);/DisplayText;;record;;rec-number;288;/rec-number;;foreign-keys;;key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521712964″;288;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Bonavia, A.;/author;;author;Singbartl, K.;/author;;/authors;;/contributors;;auth-address;Department of Anesthesiology and Perioperative Medicine, PennState Health-Milton S. Hershey Medical Center, Hershey, PA, USA. Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ, 85054, USA. [email protected];/auth-address;;titles;;title;A review of the role of immune cells in acute kidney injury;/title;;secondary-title;Pediatr Nephrol;/secondary-title;;/titles;;periodical;;full-title;Pediatr Nephrol;/full-title;;/periodical;;edition;2017/08/13;/edition;;keywords;;keyword;Acute kidney injury;/keyword;;keyword;Immune system dysfunction;/keyword;;/keywords;;dates;;year;2017;/year;;pub-dates;;date;Aug 11;/date;;/pub-dates;;/dates;;isbn;1432-198X (Electronic) 0931-041X (Linking);/isbn;;accession-num;28801723;/accession-num;;urls;;related-urls;;url;https://www.ncbi.nlm.nih.gov/pubmed/28801723;/url;;/related-urls;;/urls;;electronic-resource-num;10.1007/s00467-017-3774-5;/electronic-resource-num;;/record;;/Cite;;/EndNote;(23). This test is relayed on the use of antigens in the surface receptor, hence will help label a specific target antigen with fluorescence dye PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb25hdmlhPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA (10, 23).

PAS staining
PAS staining will be done using the PAS Kit according to the protocol of the manufacturer, which will help with regards to evaluating histological damage in kidney proximal tubules. Kidney damage in the cortical proximal will be scored as the approximate extent of tubules that display tubular necrosis, cast formation and tubular dilation as follows: 0=normal; 1=10%; 2=10–25%; 3=26–50%; 4=51–75%; 5=75–95%; 6=;96%) ADDIN EN.CITE ;EndNote;;Cite;;Author;Meng;/Author;;Year;2018;/Year;;RecNum;296;/RecNum;;DisplayText;(10);/DisplayText;;record;;rec-number;296;/rec-number;;foreign-keys;;key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521773040″;296;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Meng, X. M.;/author;;author;Ren, G. L.;/author;;author;Gao, L.;/author;;author;Yang, Q.;/author;;author;Li, H. D.;/author;;author;Wu, W. F.;/author;;author;Huang, C.;/author;;author;Zhang, L.;/author;;author;Lv, X. W.;/author;;author;Li, J.;/author;;/authors;;/contributors;;auth-address;School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. Anhui Institute of Innovative Drugs, Hefei, Anhui, China. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China. Huainan First People;apos;s Hospital and First Affiliated Hospital of Anhui University of Science ;amp; Technology, Huainan, Anhui, China.;/auth-address;;titles;;title;NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation;/title;;secondary-title;Lab Invest;/secondary-title;;/titles;;periodical;;full-title;Lab Invest;/full-title;;/periodical;;pages;63-78;/pages;;volume;98;/volume;;number;1;/number;;edition;2017/11/07;/edition;;dates;;year;2018;/year;;pub-dates;;date;Jan;/date;;/pub-dates;;/dates;;isbn;1530-0307 (Electronic) 0023-6837 (Linking);/isbn;;accession-num;29106395;/accession-num;;urls;;related-urls;;url;https://www.ncbi.nlm.nih.gov/pubmed/29106395;/url;;/related-urls;;/urls;;electronic-resource-num;10.1038/labinvest.2017.120;/electronic-resource-num;;/record;;/Cite;;/EndNote;(10).

Immunohistochemical analysis
Immunohistochemical analysis will be performed in paraffin sections, which helps to examine renal damage and inflammation. Sections of tissue will be incubated with primary antibody (rabbit anti-KIM-1 and anti-TNF-) ADDIN EN.CITE ;EndNote;;Cite;;Author;Han;/Author;;Year;2002;/Year;;RecNum;302;/RecNum;;DisplayText;(22);/DisplayText;;record;;rec-number;302;/rec-number;;foreign-keys;;key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1521846414″;302;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Han, W. K.;/author;;author;Bailly, V.;/author;;author;Abichandani, R.;/author;;author;Thadhani, R.;/author;;author;Bonventre, J. V.;/author;;/authors;;/contributors;;auth-address;Medical Services, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.;/auth-address;;titles;;title;Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury;/title;;secondary-title;Kidney Int;/secondary-title;;/titles;;periodical;;full-title;Kidney Int;/full-title;;/periodical;;pages;237-44;/pages;;volume;62;/volume;;number;1;/number;;edition;2002/06/26;/edition;;keywords;;keyword;Acute Kidney Injury/diagnosis/urine;/keyword;;keyword;Aged;/keyword;;keyword;Aged, 80 and over;/keyword;;keyword;Biomarkers;/keyword;;keyword;Cell Adhesion Molecules/*urine</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Kidney Tubular Necrosis, Acute/urine</keyword><keyword>Kidney Tubules, Proximal/*pathology</keyword><keyword>Male</keyword><keyword>*Membrane Proteins</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2002</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0085-2538 (Print) 0085-2538 (Linking)</isbn><accession-num>12081583</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12081583</url></related-urls></urls><electronic-resource-num>10.1046/j.1523-1755.2002.00433.x</electronic-resource-num></record></Cite></EndNote>(22) antibody overnight at 4C. Following incubation in the secondary antibody and chromagen liquid DAB (3, 30-diaminobenzide tetrahydrochloride) – detects secondary antibody, the slides are then counterstained with haematoxylin – detects the nucleus. Non-immune rabbit IgG instead of primary antibody will be used as negative control.

Measurement of tension
To study the endothelium intact artery; vessel will be extracted carefully from connective tissue, because the endothelium is damaged easily from the mechanical stress caused from isolation, mounting wire or cannulation ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). In order to determine endothelium dependent relaxation, vessels will be pre-constricted with thromboxane, typically at a concentration of 10-6M ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). Acetylcholine is administered for cumulative relaxation curve at concentrations ranging between 10-9M – 10-5M ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24).

Organ Bath
This is a traditional method used to investigate the physiology and pharmacology of isolated vessels ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). An isometric measurement is mostly used to measure vascular contractility as the vessel length remains constant ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). Thus this method of measurement is used to monitor tension in small tissue strips and rings (100m diameter) to large preparations ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). Appropriate hooks are selected depending on the diameter of the vessel; ring segments are cut and two tungsten hooks are carefully passed through the lumen of arterial vessel in organ bath containing Krebs solution ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). Temperature is maintained at 37C and continuously aerated with 100% O2 ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24). One hook is attached to a displacement device, which allows to manually adjust the tension of the vessel and the other hook connected to an isometric transducer ADDIN EN.CITE <EndNote><Cite><Author>Ko</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText>(24)</DisplayText><record><rec-number>385</rec-number><foreign-keys><key app=”EN” db-id=”5pv9r0ape50paleas0dppreydvtsazrf052f” timestamp=”1524475254″>385</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ko, E. A.</author><author>Song, M. Y.</author><author>Donthamsetty, R.</author><author>Makino, A.</author><author>Yuan, J. X.</author></authors></contributors><auth-address>Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612.</auth-address><titles><title>Tension Measurement in Isolated Rat and Mouse Pulmonary Artery</title><secondary-title>Drug Discov Today Dis Models</secondary-title></titles><periodical><full-title>Drug Discov Today Dis Models</full-title></periodical><pages>123-130</pages><volume>7</volume><number>3-4</number><edition>2010/01/01</edition><dates><year>2010</year></dates><isbn>1740-6757 (Print) 1740-6757 (Linking)</isbn><accession-num>23175638</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23175638</url></related-urls></urls><custom2>PMC3501740</custom2><electronic-resource-num>10.1016/j.ddmod.2011.04.001</electronic-resource-num></record></Cite></EndNote>(24).

Statistics
The project is a basic study, and statistics will be performed by two-way ANOVA and appropriate post hoc test (Dunnets, Bonferroni) correction for multiple comparisons of the mean at a 95% confidence level. To detect a minimum 50% change in BUN or sCr in mice with a standard deviation of 15 and p<0.05, a 93% Power is expected with n=12. For detection of minimum 30% change in blood vessel function with a standard deviation of 30% and p<0.05; 82% Power is expected with n=12. And to detect a minimum 25% reduction in PAS staining (marker of kidney damage), with a standard deviation of 1 (10%) and p<0.05 resulting in 88% Power is expected with n=12.

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