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Tacrolimus-Induced Hypertension and Nephrotoxicity in Fawn-Hooded Rats Are Attenuated by Dual Inhibition of Renin–Angiotensin System

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Tacrolimus-Induced Hypertension and Nephrotoxicity in Fawn-Hooded Rats Are Attenuated by Dual Inhibition of Renin–Angiotensin System Hypertension Research (2014) 37, 724–732 & 2014 The Japanese Society of Hypertension All rights reserved 0916-9636/14 www.nature.com/hr ORIGINAL ARTICLE Tacrolimus-induced hypertension and nephrotoxicity in Fawn-Hooded rats are attenuated by dual inhibition of renin–angiotensin system Lenka Hosˇkova´1, Ivan Ma´lek1, Josef Kautzner1, Eva Honsova´2, Richard P E van Dokkum3, Zuzana Huskova´4, Alzˇbeta Vojtı´sˇkova´4,Sˇa´rka Varcabova´4, LudeˇkCˇ ervenka4 and Libor Kopkan4 Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin–angiotensin system (RAS) and other antihypertensive treatment on blood pressure and renal function in normotensive and hypertensive Fawn-Hooded (FH) strains during chronic calcineurin inhibitor (CNI) administration. Combinations of perindopril (5 mg kg À1 per day) and losartan (50 mg kg À1 per day) or amlodipine (6 mg kg À1 per day) and metoprolol (80 mg kg À1 per day) were administered to normotensive (FHL) and hypertensive (FHH) rats, fed with diet containing tacrolimus (Tac; 12 mg kg À1 per day). Tac-induced arterial hypertension in both animal strains (FHL: 151±4; FHH: 198±6 mm Hg) was prevented by dual RAS inhibition (FHL: 132±3 mm Hg, Po0.05; FHH: 153±3 mm Hg, Po0.05) as well as by a combination of amlodipine and metoprolol (FHL: 136±3 mm Hg, Po0.05; FHH: 166±4 mm Hg, Po0.05). However, significant nephroprotection was observed only in animals on dual RAS inhibition where albuminuria was reduced in both FHL (51.1±3.9 vs. 68.3±4.5 lg per day; Po0.05) and FHH rats (13.1±0.3 vs. 18.8±0.7 mg per day; Po0.05). We also found Tac-induced enhancement in renal angiotensin II activity that was significantly reduced by dual RAS inhibition in both FHL (63.5±3.2 vs. 23.1±3.0 fmol g À1) and FHH (79.8±8.5 vs. 32.2±5.8 fmol g À1). In addition, histological analysis revealed that RAS inhibition noticeably diminished glomerulosclerosis and tubulo-interstitial injury. This study indicates that dual blockade of RAS significantly attenuates Tac-induced arterial hypertension and nephrotoxicity in FH rats and further supports the notion that RAS inhibitors display efficient renoprotective properties during CNI treatment. Hypertension Research (2014) 37, 724–732; doi:10.1038/hr.2014.79; published online 10 April 2014 Keywords: arterial hypertension; calcineurin inhibitor; Fawn-Hooded rat; nephrotoxicity; renin–angiotensin system INTRODUCTION increased incidence of arterial hypertension10 and activation of several The use of calcineurin inhibitors (CNIs) in transplantation of solid systems involved in the progression of renal damage.2–4 However, the organs is commonly associated with development of arterial hyper- exact mechanisms underlying the development of CNI-induced tension and nephrotoxicity.1–4 The incidence of hypertension after hypertension and nephrotoxicity are not fully understood. transplantation remains high, despite considerable progress in It is generally accepted that combination of antihypertensive drugs immunosuppressive therapy. Several pathophysiological mech- results in better blood pressure control and organoprotection, both anisms, including direct vasoconstriction, impaired vasodilatation in patients with various cardiovascular and renal diseases and and sodium-retaining effects, have been proposed to underlie CNI- in transplant recipients.11–14 In addition, several studies have associated hypertension.3,4 CNI-induced direct renal vasoconstrictive demonstrated that dual RAS combination therapy—angiotensin- effects reduce glomerular filtration and renal blood flow, and the converting enzyme inhibitors (ACEI) and angiotensin II (ANG II) resulting hypoperfusion may subsequently activate the renin– receptor blocker (ARB)—shows further benefits both in hypertensive angiotensin system (RAS), particularly in the kidney.2,5–7 Moreover, patients with chronic renal disease15 or with congestive heart failure.16 recent studies have shown that CNIs increase the activity of sodium However, there is no evidence for the efficacy of dual RAS inhibition transport along the nephrons.4,8,9 As a result, chronic administration on Tac-induced hypertension and nephrotoxicity. Furthermore, there of CNIs could compromise normal renal function that contributes to is also lacking comparison of renoprotective activity against CNIs 1Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 3Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands and 4Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Correspondence: Dr L Kopkan, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. E-mail: [email protected] Received 9 August 2013; revised 3 February 2014; accepted 1 March 2014; published online 10 April 2014 Tacrolimus effect in Fawn-Hooded rats and RAS LHosˇkova´ et al 725 with other combined antihypertensive regimen such as calcium (3) FHL CCB/BB (n ¼ 6), channel blocker (CCB) together with beta blocker (BB). (4) FHL Tac (n ¼ 8), The Fawn-Hooded (FH) rat strains were inbred and selected for (5) FHL Tac þ ACEI/ARB (n ¼ 6), high blood pressure and denoted accordingly as FH hypertensive (6) FHL Tac þ CCB/BB (n ¼ 6); (FHH) or FH low blood pressure (FHL) rats. In contrast to FHL, FHH rats develop early hypertension and exhibit the increased and six groups of FHH animals on standard or Tac diet: susceptibility to renal disease due to impaired autoregulatory effi- (1) FHH-untreated control (n ¼ 6), ciency of the kidney17–19 that leads to glomerular hypertension, 18,20,21 (2) FHH ACEI/ARB (n ¼ 6), hyperfiltration and proteinuria. Hypertension and proteinuria (3) FHH CCB/BB (n ¼ 6); 21,22 increase further with age, and the progression of renal damage (4) FHH Tac (n ¼ 8), results in premature death from end-stage renal failure in these (5) FHH Tac þ ACEI/ARB (n ¼ 8), animals.20 This rat strain therefore represents a unique model of (6) FHH Tac þ CCB/BB (n ¼ 6). intrinsic human chronic kidney disease (CKD) more closely.23 Therefore, it is of clinical importance to evaluate the effect of long- Systolic blood pressure (SBP) was monitored by tail-cuff plethysmography term CNI treatment in CKD condition and assess the optimum (MC 4000; Hatteras Instruments, Cary, NC, USA) regularly during the antihypertensive therapy that exhibits sufficient renoprotection 4-month experimental period. In accordance with recommendations for blood 27 against CNI nephrotoxicity. pressure measurements in experimental animals, which is adequate for Thus, in the present study, we hypothesized that efficient anti- detecting intergroup differences in SBP over time, and therefore is optimal for long-term studies. This method is regularly used in our laboratory24–26 where a hypertensive treatment may prevent blood pressure increase and renal correlation between measurements by noninvasive plethysmography technique injury induced by chronic CNI treatment in a model of CKD and and direct blood pressure measurements was previously validated. Although genetic hypertension. The specific aim of this study was to determine the radiotelemetry system is preferred to obtain all blood pressure parameters whether dual RAS blockade (ACEI and ARB combination) attenuates in experimental animals, this approach is not suitable for such long-term CNI-induced hypertension and nephrotoxicity in FH strains that were studies. under chronic Tac medication. In addition, other antihypertensive Urine and blood collections were performed every 4 weeks of the treatment treatment, a combination of CCB with BB, was also used to determine to determine albuminuria and plasma creatinine (PCr) concentration by the possible attenuation of CNI effects in FH strains without commercially available kits (Assaypro LLC, St Charles, MO, USA; Cayman affecting RAS. Chemical Company, Ann Arbor, MI, USA, respectively), as described previously.26,28 In addition, changes in urinary angiotensinogen (AGT) and METHODS aldosterone were also assessed by specific sandwich enzyme-linked immunosorbent assay and radioimmunoassay kits, respectively, (IBL The study was performed in male rats of two FH strains (normotensive FHL International GmbH, Hamburg, Germany; Immunotech, Marseille, France). and hypertensive FHH animals) in accordance with the guidelines and At least twice before starting measurements, rats were accustomed to the practices established by the Institute for Clinical and Experimental Medicine procedure of tail-cuff SBP measurements and metabolic cages. At the end of Animal Care and Use Committee and in accordance with the law in the Czech experiments, animals were decapitated to collect whole blood and harvest the Republic. Both FH strains were originally provided by RPE van Dokkum tissues for RAS peptide measurements and histological analysis. The full (The University of Groningen) to establish our colony. The animals used in the blood was collected into two separate pre-chilled test tubes with specific present study were housed in the institutional facility accredited by the Czech inhibitors. For ANG II assays, the blood samples were immediately mixed with Association for Accreditation of Laboratory Animal Care. the recommended reagents: 5 mM
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