||Efficacy and Mechanism of Sesame Oil on Chronic Kidney Disease-induced Cardiac Hypertrophy
||Institute of Environmental and Occupational Health
chronic kidney disease
left ventricular hypertrophy
慢性腎臟疾病會導致腎功能惡化且造成不可逆的損害，氧化壓力及纖維化和慢性腎病的發展關係非常密切。臨床上，低血鉀及高血壓是導致慢性腎病病患，罹患心血管疾病及死亡的重要因子。慢性腎病所引發的長期性低血鉀及高血壓，將促使左心室肥大發生，進而提升心因性疾病的發病率及死亡率，是導致心臟衰竭的重要風險因子。腎素-血管收縮素系統所活化的絲裂原活化蛋白激酶及氧化壓力，在左心室肥大的病理發展過程中扮演重要的角色。芝麻油是天然又營養豐富的抗氧化物，能保護腎臟免於多種腎病損傷，且具有抗高血壓的潛力。本研究探討芝麻油治療慢性腎病引發之心肌肥大的功效及其機轉。老鼠給予單側腎臟切除，持續五週每週兩次，注射醋酸去氧皮脂酮 (15 毫克/毫升/千克體重，溶於礦物油中)，並在飲用水中添加1%氯化鈉，來誘導慢性腎病引發左心室肥大的動物模式；由於誘導動物模式的第四週開始產生腎功能下降及高血壓，自第五週開始連續一週給予動物芝麻油(0.5，1 毫升/千克體重/天)，第五週結束取得老鼠血液、心臟及腎臟組織，評估芝麻油對慢性腎病鼠的腎功能及左心室肥大的治療效果。結果顯示，芝麻油顯著降低慢性腎病鼠的血中尿素氮、肌酸酐、排尿量、蛋白尿、腎臟羥基自由基、過氧亞硝酸、脂質過氧化、骨橋蛋白及膠原蛋白的沉積；增加肌酸酐清除率及核內Nrf2的表現；有效抑制慢性腎病鼠的收縮壓及舒張壓、心電圖異常、心臟重量、左心室厚度、心肌細胞大小；提升血中鉀鎂離子濃度；降低慢性腎病鼠的心臟中腎素-血管收縮素系統、氧化壓力及絲裂原活化蛋白激酶的活化。總結，芝麻油能透過降低腎臟氧化壓力及纖維化，改善慢性腎病鼠的腎功能缺失；並且經由抑制低血鉀、心臟中腎素-血管收縮素系統調控的絲裂原活化蛋白激酶的活化及氧化壓力，達到改善慢性腎病鼠左心室肥大的功效。
Chronic kidney disease (CKD) causes a progressive and irreversible loss of renal function. Oxidative stress and fibrosis are highly related to the progression of CKD. Hypokalemia and hypertension in CKD patients are common manifestation of preclinical cardiovascular conditions that have a predictive value for cardiovascular morbidity and mortality. Left ventricular hypertrophy (LVH), an important risk factor in heart failure, is attributed to long-term hypokalemia and hypertension in CKD. The renin-angiotensin system (RAS) is involved in the development of LVH by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a natural nutrient-rich and potent antioxidant protects the kidney in many renal disorders, and possesses potent anti-hypertensive activities. We examined the efficacy and mechanism of sesame oil on cardiac hypertrophy in CKD. We induced LVH using a CKD model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uni-nephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Sesame oil significantly decreased blood urea nitrogen, creatinine, urine volume, and albuminuria in DOCA/salt-treated rats. Sesame oil significantly decreased renal hydroxyl radical, peroxynitrite level, lipid peroxidation, osteopontin, and collagen deposition, but increased creatinine clearance rate and nuclear Nrf2 expression in DOCA/salt-treated rats. In addition, sesame oil effectively reduced the SP/DP and ECG abnormality, the heart mass, the thickness of left ventricle, and the size of cardiomyocytes, and increased the serum levels of K+ and Mg2+ in DOCA/salt-treated rats. Furthermore, sesame oil significantly decreased the levels of cardiac RAS, oxidative stress, and down-regulated the expression of MAPKs in DOCA/salt-treated rats. We conclude that sesame oil mitigates renal dysfunction by inhibiting renal oxidative stress and fibrosis; attenuates LVH by regulating hypokalemia and decreasing cardiac RAS-mediated MAPK activation in CKD rats.
Abstract in Chinese............I
1.1. Chronic kidney disease (CKD) .........1
1.2. Renal oxidative stress in CKD.........1
1.3. Renal fibrosis in CKD.........2
1.4. Left ventricular hypertrophy (LVH) in CKD.....3
1.5. Hypokalemia in CKD-induced LVH.......3
1.6. Activation of renin-angiotensin system (RAS) in CKD-induced LVH....4
1.7. Sesame oil............5
1.8. The aim of the study...........6
2. Experimental design..........7
2.1. Time-course study of DOCA/salt-induced CKD in rats......7
2.2. Effect of sesame oil on LVH in DOCA/salt-treated rats......7
3. Materials and methods...........9
3.1.4. ELISA assay kits........12
3.1.7. Computer software.........15
3.2.2. Inducing LVH...........15
3.2.3. Assessing renal function........16
3.2.4. Hemodynamic and functional measurements......16
3.2.5. Assessing electrolyte levels.......16
3.2.6. Estimating heart weight/100 g body weight ratio.....17
3.2.7. Histological evaluation of renal injury and cardiac hypertrophy....17
3.2.8. Measuring hydroxyl radical, peroxynitrite, and superoxide anion in renal and heart tissue.........18
3.2.9. Measuring renal and heart lipid peroxidation....18
3.2.10. Measuring heart nitric oxide levels......19
3.2.11. Immunohistochemical staining of Nrf2.....19
3.2.12. Determining renal OPN expression......19
3.2.13. Evaluating renal fibrosis.......20
3.2.14. Quantifying Nrf2, renin, ACE, Ang II, AT1R, p47-phox, ERK, JNK, p38, and ASK1 expression.........20
3.2.15. Measuring c-Fos and c-Jun mRNA expression......21
3.2.16. Protein assay..........22
3.2.17. Statistical analyses.........22
4.1. Time course of DOCA/salt-induced renal dysfunction and hypertension in rats...........23
4.2. Therapeutic effects of sesame oil on renal dysfunction in DOCA/salt-treated rats...........23
4.3. Therapeutic effects of sesame oil on renal histological change in DOCA/salt-treated rats............23
4.4. Therapeutic effects of sesame oil on renal oxidative stress in DOCA/salt-treated rats..........24
4.5. Therapeutic effects of sesame oil on renal Nrf2 expression in DOCA/salt-treated rats............24
4.6. Therapeutic effects of sesame oil on OPN expression in DOCA/salt-treated rats............25
4.7. Therapeutic effects of sesame oil on renal fibrosis in DOCA/salt-treated rats............25
4.8. Therapeutic effects of sesame oil on cardiac function in DOCA/salt-treated rats ...........25
4.9. Therapeutic effects of sesame oil on serum K+ and Mg2+ levels in DOCA/salt-treated rats..........25
4.10. Therapeutic effects of sesame oil on cardiac hypertrophy in DOCA/salt-treated rats...........26
4.11. Therapeutic effects of sesame oil on systemic RAS in DOCA/salt-treated rats............26
4.12. Therapeutic effects of sesame oil on cardiac RAS in DOCA/salt-treated rats............27
4.13. Therapeutic effects of sesame oil on cardiac AT1R expression in DOCA/salt-treated rats...........27
4.14. Therapeutic effects of sesame oil on cardiac MAPK signal transduction in DOCA/salt-treated rats.........28
4.15. Therapeutic effects of sesame oil on cardiac c-Fos and c-Jun mRNA expression in DOCA/salt-treated rats.......28
4.16. Therapeutic effects of sesame oil on cardiac oxidative stress in DOCA/salt-treated rats...........28
4.17. Therapeutic effects of sesame oil on the expression of ASK1 in DOCA/salt-treated rats...........29
Table & Figures...........51
Abdelhamid G, El-Kadi AO. Buthionine sulfoximine, an inhibitor of glutathione biosynthesis, induces expression of soluble epoxide hydrolase and markers of cellular hypertrophy in a rat cardiomyoblast cell line: roles of the NF-κB and MAPK signaling pathways. Free Radic Biol Med. 2015; 82: 1-12.
Abdou HM, Hussien HM, Yousef MI. Deleterious effects of cypermethrin on rat liver and kidney: protective role of sesame oil. J Environ Sci Health B. 2012; 47: 306-14.
Akita M, Kuwahara M, Tsubone H et al. ECG changes during furosemide-induced hypokalemia in the rat. J Electrocardiol. 1998; 31: 45-49.
Aoyagi K, Akiyama K, Shahrzad S et al. Formation of guanidinosuccinic acid, a stable nitric oxide mimic, from argininosuccinic acid and nitric oxide-derived free radicals. Free radical research. 1999; 31: 59-65.
Ash S, Campbell KL, Bogard J, Millichamp A. Nutrition prescription to achieve positive outcomes in chronic kidney disease: a systematic review. Nutrients. 2014; 6: 416-51.
Asmar A, Mohandas R, Wingo CS. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012; 60: 492-7.
Benigni A, Corna D, Zoja C et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009; 119: 524-30.
Bianciotti LG, De Bold AJ. Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor. Am J Physiol Heart Circ Physiol. 2002; 282: 1127-34.
Boshtam M, Rafiei M, Sadeghi K, Sarraf-Zadegan N. Vitamin E can reduce blood pressure in mild hypertensives. Int J Vitam Nutr Res. 2002; 72: 309-14.
Brown RA, Chipperfield AR, Davis JP, Harper AA. Increased (Na+K+Cl) cotransport in rat arterial smooth muscle in deoxycorticosterone (DOCA)/salt-induced hypertension. J Vasc Res. 1999; 36: 492-501.
Chandrasekaran VR, Chien SP, Hsu DZ, Chang YC, Liu MY. Effects of sesame oil against after the onset of acetaminophen-induced acute hepatic injury in rats. JPEN J Parenter Enteral Nutr. 2010; 34: 567-73.
Coca SG, Perazella MA, Buller GK. The cardiovascular implications of hypokalemia. Am J Kidney Dis. 2005; 45: 233-47.
Copple IM, Goldring CE, Kitteringham NR, Park BK. The Nrf2-Keap1 defense pathway: role in protection against drug-induced toxicity. Toxicology. 2008; 246: 24-33.
Coresh J, Selvin E, Stevens LA et al. Prevalence of chronic kidney disease in the United States. JAMA: the journal of the American Medical Association. 2007; 298: 2038-47.
Cuzzocrea S, Mazzon E, Dugo L et al. A role for superoxide in gentamicin-mediated nephropathy in rats. Eur J Pharmacol. 2002; 450: 67-76.
Date MO, Morita T, Yamashita N et al. The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vitro murine pressure-overload model. J Am Coll Cardiol. 2002; 39: 907-12.
Denhardt DT, Noda M, O'Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. The Journal of clinical investigation. 2001; 107: 1055-61.
Elnakish MT, Moldovan L, Khan M, Hassanain HH, Janssen PM. Myocardial Rac1 Exhibits Partial Involvement in Thyroxin-Induced Cardiomyocyte Hypertrophy and its Inhibition is Not Sufficient to Improve Cardiac Dysfunction or Contractile Abnormalities in Mouse Papillary Muscles. J Cardiovasc Pharmacol. 2013; 61: 536-44.
Erdely A, Freshour G, Tain YL, Engels K, Baylis C. DOCA/NaCl-induced chronic kidney disease: a comparison of renal nitric oxide production in resistant and susceptible rat strains. Am J Physiol Renal Physiol. 2007; 292: 192-6.
Gang C, Qiang C, Xiangli C, Shifen P, Chong S, Lihong L. Puerarin suppresses angiotensin ii-induced cardiac hypertrophy by inhibiting NADPH oxidase activation and oxidative stress-triggered AP-1 signaling pathways. J Pharm Pharm Sci. 2015; 18: 235-48.
Ghali JK, Anand IS, Abraham WT et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008; 117: 526-35.
Go AS, Mozaffarian D, Roger VL et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013; 127: e6-e245.
Gonza´ lez A, Lo´ pez B, Dı´ez J. Fibrosis in hypertensive heart disease: role of the renin-angiotensin-aldosterone system. Med Clin North Am. 2004; 88: 83-97.
Gonzalez AA, Prieto MC. Renin and the (pro) renin receptor in the renal collecting duct: Role in the pathogenesis of hypertension. Clin Exp Pharmacol Physiol. 2015; 42: 14-21.
Green DM, Ropper AH, Kronmal RA, Psaty BM, Burke GL. Serum potassium level and dietary potassium intake as risk factors for stroke. Neurology. 2002; 59: 314-20.
Grobe JL, Mecca AP, Lingis M et al. Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7). Am J Physiol Heart Circ Physiol. 2007; 292: 736-42.
Hamada N, Tanaka A, Fujita Y et al. Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against H2O2-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds. Bioorganic & medicinal chemistry. 2011; 19: 1959-65.
Hartner A, Porst M, Gauer S, Pröls F, Veelken R, Hilgers KF. Glomerular osteopontin expression and macrophage infiltration in glomerulosclerosis of DOCA-salt rats. Am J Kidney Dis. 2001; 38: 153-64.
He FJ, MacGregor GA. Beneficial effects of potassium on human health. Physiol Plant. 2008; 133: 725-35.
Hirotani S, Otsu K, Nishida K et al. Involvement of nuclear factor-kB and apoptosis signal-regulated kinase 1 and G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy. Circulation. 2002; 105: 509-15.
Hsu CY. Linking the population epidemiology of acute renal failure, chronic kidney disease and end-stage renal disease. Curr Opin Nephrol Hy. 2007; 16: 221-6.
Hsu DZ, Li YH, Chu PY, Periasamy S, Liu MY. Sesame oil prevents acute kidney injury induced by the synergistic action of aminoglycoside and iodinated contrast in rats. Antimicrob Agents Chemother. 2011; 55: 2532-6.
Hsu DZ, Liu CT, Li YH, Chu PY, Liu MY. Protective effect of daily sesame oil supplement on gentamicin-induced renal injury in rats. Shock. 2010; 33: 88-92.
Hsu DZ, Liu MY. Sesame oil attenuates multiple organ failure and increases survival rate during endotoxemia in rats. Critical care medicine. 2002; 30: 1859-62.
Hsu DZ, Chien SP, Chen KT, Liu MY. The effect of sesamol on systemic oxidative stress and hepatic dysfunction in acutely iron-intoxicated mice. Shock. 2007; 28: 596-601.
Hsu, DZ, Li YH, Chu PY, Chien SP, Chuang YC, Liu MY. Attenuation of endotoxin-induced oxidative stress and multiple organ injury by 3,4-methylenedioxyphenol in rats. Shock. 2006; 25: 300-5.
Huang CL, Kuo E. Mechanism of Hypokalemia in Magnesium Deficiency. J Am Soc Nephrol. 2007; 18: 2649-52.
Huang Y, Zhou Q, Haaijer-Ruskamp FM, Postma MJ. Economic evaluations of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in type 2 diabetic nephropathy: a systematic review. BMC Nephrol. 2014; 15: 15.
Irita J, Okura T, Jotoku M et al. Osteopontin deficiency protects against aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney. Am J Physiol Renal Physiol. 2011; 301: 833-44.
Iwazu Y, Muto S, Hirahara I, Fujisawa G, Takeda S, Kusano E. Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats. J Hypertens. 2011; 29: 2440-53.
Kim S, Iwao H. Activation of mitogen-activated protein kinases in cardiovascular hypertrophy and remodeling. Jpn J Pharmacol. 1999; 80: 97-102.
Kim S, Kawamura M, Wanibuchi H et al. Angiotensin II type I receptor blockade inhibits the expression of immediate early genes and fibronectin in rat injured artery. Circulation. 1995; 92: 88-95.
Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutation research. 2010; 690: 12-23.
Klingel K and Kandolf R. Osteopontin: a biomarker to predict the outcome of inflammatory heart disease. Semin Thromb Hemost. 2010; 36: 195-202.
Kuo HW, Tsai SS, Tiao MM, Yang CY. Epidemiological features of CKD in Taiwan. American journal of kidney diseases. 2007; 49, 46-55.
Lahera V, Goicoechea M, de Vinuesa SG et al. Oxidative stress in uremia: the role of anemia correction. J Am Soc Nephrol. 2006; 17: 174-7.
Laragh JH, Sealey JE. K+ depletion and the progression of hypertensive disease or heart failure: the pathogenic role of diuretic-induced aldosterone secretion. Hypertension. 2001; 37: 806-10.
Li JM, Gall NP, Grieve DJ, Chen M, Shah AM. Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension. 2002; 40: 477-84.
Li W, Khor TO, Xu C et al. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008; 76: 1485-9.
Lijnen PJ, Petrov VV. Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. Methods Find Exp Clin Pharmacol. 2003; 25: 541-64.
Makowski K, Gielerak G, Kramarz E et al. Left ventricular diastolic dysfunction is associated with impaired baroreflex at rest and during orthostatic stress in hypertensive patients with left ventricular hypertrophy. J Hum Hypertens. 2013; 27: 465-73.
Martin M, Kopaliani I, Jannasch A et al. Antihypertensive and cardioprotective effects of the dipeptide isoleucine-tryptophan and whey protein hydrolysate. Acta Physiol (Oxf). 2015. [Epub ahead of print]
Materson BJ, Cushman WC, Goldstein G et al. Treatment of hypertension in the elderly: I. Blood pressure and clinical changes. Results of a Department of Veterans Affairs cooperative study. Hypertension. 1990; 15: 348-60.
Matsui H, Shimosawa T, Uetake Y, et al. Protective effect of potassium against the hypertensive cardiac dysfunction: Association with reactive oxygen species reduction. Hypertension. 2006; 48: 225-31.
Matsumura Y, Kita S, Tanida Y, et al. Antihypertensive effect of sesamin III Protection against development and maintenance of hypertension in stroke-prone spontaneously hypertensive rats. Biol Pharm Bull. 1998; 21: 469-73.
Mensah GA, Pappas TW, Koren MJ, Ulin RJ, Laragh JH, Devereux RB. Comparison of classification of the severity of hypertension by blood pressure level and by World Health Organization criteria in the prediction of concurrent cardiac abnormalities and subsequent complications in essential hypertension. J Hypertens. 1993; 11: 1429-40.
Meredith PA. Angiotensin II receptor antagonists alone and combined with hydrochlorothiazide: Potential benefits beyond the antihypertensive effect. Am J Cardiovasc Drugs. 2005; 5: 171-83.
Nakamura K, Fushimi K, Kouchi H et al. Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-kB and angiotensin II. Circulation. 1998; 98: 798-9.
Nakamura H, Honda H, Inada Y et al. Osteopontin expression in vascular smooth muscle cells in patients with end-stage renal disease. Ther Apher Dial. 2006; 10: 273-7.
Nakano D, Itoh C, Takaoka M, Kiso Y, Tanaka T, Matsumura Y. Antihypertensive effect of sesamin. IV. Inhibition of vascular superoxide production by sesamin. Biol Pharm Bull. 2002; 25: 1247-9.
Namiki M. Nutraceutical functions of sesame: a review. Crit Rev Food Sci Nutr. 2007; 47: 651-73.
Nemoto S, Sheng Z, Lin A. Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy. Mol Cell Biol. 1998; 18: 3518-26.
Newaz MA, Nawal NNA. Effect of α-tocopherol on lipid peroxidation and total antioxidant status in spontaneously hypertensive rats. Am J Hypertens. 1998; 11: 1480-5.
Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002; 109: 1417-27.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009; 284: 13291-5.
Noguchi T, Ikeda K, Sakai Y et al. Effects of vitamin E and sesamin on hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Hypertens Res. 2001; 24: 735-24.
Obata T. Nitric oxide and depolarization induce hydroxyl radical generation. Jpn J Pharmacol. 2002; 88: 1-5.
Obiefuna I, Young R. Concurrent administration of aqueous Azadirachta indica (neem) leaf extract with DOCA-salt prevents the development of hypertension and accompanying electrocardiogram changes in the rat. Phytother Res. 2005; 19: 792-5.
Okin PM, Hille DA, Kjeldsen SE et al. Greater regression of electrocardiographic left ventricular hypertrophy during hydrochlorothiazide therapy in hypertensive patients and the interaction with losartan vs atenolol therapy: The LIFE Study. Am J Hypertens. 2010; 23: 786-93.
Okin PM, Kjeldsen SE, Lindholm LH, Dahlöf B, Devereux RB. The relationship of electrocardiographic left ventricular hypertrophy to decreased serum potassium. Blood Press. 2012; 21: 146-152.
Omura T, Yoshiyama M, Yoshida K et al. Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine. Hypertension. 2002; 39:81-6.
Ophascharoensuk V, Giachelli CM, Gordon K et al. Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int. 1999; 56: 571-80.
Palm F, Nordquist L. Renal tubulointerstitial hypoxia: cause and consequence of kidney dysfunction. Clin Exp Pharmacol Physiol. 2011; 38: 424-30.
Parving HH, Brenner BM, McMurray JJ et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012; 367: 2204-13.
Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006: 86: 747-803.
Pergola PE, Krauth M, Huff JW et al. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. American journal of nephrology. 2011; 33: 469-76.
Periasamy S, Hsu DZ, Chandrasekaran VR, Liu MY. Sesame Oil Accelerates Healing of 2,4,6-Trinitrobenzenesulfonic Acid-Induced Acute Colitis by Attenuating Inflammation and Fibrosis. JPEN J Parenter Enteral Nutr. 2013; 37:674-82.
Periasamy S, Mo FE, Chen SY, Chang CC, Liu MY. Sesamol attenuates isoproterenol-induced acute myocardial infarction via inhibition of matrix metalloproteinase-2 and -9 expression in rats. Cell Physiol Biochem. 2011; 27: 273-80.
Periasamy S, Liu CT, Hsu DZ, Liu MY. Sesame oil accelerates kidney healing following gentamicin-induced kidney injury in rats. Am J Nephrol. 2010; 32: 383-92.
Periasamy S, Yang SS, Chen SY, Chang CC, Liu MY. Prophylactic sesame oil attenuates sinusoidal obstruction syndrome by inhibiting matrix metalloproteinase-9 and oxidative stress. JPEN J Parenter Enteral Nutr. 2013; 37: 529-37.
Pikikidou MI, Lasaridis AN, Sarafi dis PA, et al. Blood pressure and serum potassium levels in hypertensive patients receiving or not receiving antihypertensive treatment. Clin Exper Hyper. 2007; 29: 563-73.
Ponikowski P, Anker SD, Szachniewicz J et al. Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2007; 49: 753-62.
Ray PE, Suga S, Liu XH, Huang X, Johnson RJ. Chronic potassium depletion induces renal injury, salt sensitivity, and hypertension in young rats. Kidney Int. 2001; 59: 1850-8.
Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998; 339: 1448-56.
Rodriguez-Iturbe B, Garcia Garcia G. The role of tubulointerstitial inflammation in the progression of chronic renal failure. Nephron Clin Pract. 2010; 116: 81-8.
Sabri A, Wilson BA, Steinberg SF. Dual action of the Gaq agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility. Circ Res. 2002; 90: 850-7.
Sankar D, Rao MR, Sambandam G, Pugalendi KV. Effect of sesame oil on diuretics or Beta-blockers in the modulation of blood pressure, anthropometry, lipid profile, and redox status. Yale J Biol Med. 2006; 79: 19-26.
Seija M, Baccino C, Nin N et al. Role of peroxynitrite in sepsis-induced acute kidney injury in an experimental model of sepsis in rats. Shock. 2012; 38: 403-10.
Shah BH, Catt KJ. A central role of EGF receptor transactivation in angiotensin II -induced cardiac hypertrophy. Trends Pharmacol Sci. 2003; 24: 239-44.
Shenasa M, Shenasa H, El-Sherif N. Left ventricular hypertrophy and arrhythmogenesis. Card Electrophysiol Clin. 2015; 7: 207-20.
Sim DS, Jeong MH, Song HC et al. Cardioprotective effect of fimasartan, a new angiotensin receptor blocker, in a porcine model of acute myocardial infarction. J Korean Med Sci. 2015; 30: 34-43.
Soe NN, Sowden M, Baskaran P et al. Cyclophilin A is required for angiotensin II-induced p47phox translocation to caveolae in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2013; 33: 2147-53.
Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail. 2002; 8: 132-40.
Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006; 114: 838-54.
Turner JM, Bauer C, Abramowitz MK, Melamed ML, Hostetter TH. Treatment of chronic kidney disease. Kidney Int. 2012; 81: 351-62.
Urtasun R, Lopategi A, George J et al. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin (V)(3) engagement and PI3K/pAkt/NFB signaling. Hepatology. 2012; 55: 594-608.
Van Veldhuisen DJ, Dickstein K, Cohen-Solal A et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007; 28: 2208-16.
Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008; 19: 333-45.
Wasilewska A, Taranta-Janusz K, Kuroczycka-Saniutycz E, Zoch-Zwierz W. Urinary OPN excretion in children with glomerular proteinuria. Adv Med Sci. 2011; 56: 193-9.
Whelton PK, He J, Cutler JA et al. Effects of oral potassium on blood pressure: meta-analysis of randomized controlled clinical trials. JAMA. 1997; 277: 1624-32.
Williams ME, Garg R. Glycemic management in ESRD and earlier stages of CKD. American journal of kidney diseases. 2014; 63: 22-38.
Xie Z, Liu J, Malhotra D, Sheridan T, Periyasamy SM, Shapiro JI. Effects of hypokalemia on cardiac growth. Ren fail. 2000; 22: 561-72.
Young DB, Lin H, McCabe RD. Potassium’s cardiovascular protective mechanisms. Am J Physiol. 1995; 268: 825-37.
Young DB. Potassium depletion and diastolic dysfunction. Hypertension. 2006; 48: 201-2.
Zhang M, Wang S, Mao L et al. Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1. J Neurosci. 2014; 34: 1903-15.