551443
research-article2014
JRA0010.1177/1470320314551443Journal of the Renin-Angiotensin-Aldosterone SystemAbe et al.
Original Article
Urinary angiotensin-converting enzyme 2 increases in diabetic nephropathy by angiotensin II type 1 receptor blocker olmesartan
Journal of the Renin-AngiotensinAldosterone System 2015, Vol. 16(1) 159–164 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320314551443 jra.sagepub.com
Masanori Abe1, Osamu Oikawa1, Kazuyoshi Okada1 and Masayoshi Soma1,2
Abstract Introduction: Angiotensin-converting enzyme 2 (ACE2) is a member of the renin–angiotensin system that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7). We evaluated the changes in urinary ACE2 levels in response to treatment with the angiotensin II type 1 receptor blocker olmesartan in diabetes patients with nephropathy. Materials and methods: This prospective, open-label, interventional study was conducted with 31 type 2 diabetes patients with nephropathy. After initial evaluation, patients received 20 mg/day olmesartan, which was increased to 40 mg/day over a 24-week period. Results: In diabetes patients with chronic kidney disease, olmesartan significantly increased urinary ACE2 levels independently of blood pressure and plasma aldosterone levels and reduced albuminuria, urinary liver-type fatty acid binding protein (L-FABP), and plasma aldosterone levels. Multivariable regression analysis revealed that the change in urinary L-FABP levels was an independent predictor of increased urinary ACE2 levels. Conclusion: Olmesartan may have the unique effect of increasing urinary ACE2 levels. However, whether this contributes to olmesartan’s renoprotective effect must be examined further. Keywords Angiotensin-converting enzyme 2, angiotensin II type 1 receptor blocker, chronic kidney disease, diabetic nephropathy, olmesartan Date received: 30 April 2014; accepted: 17 August 2014
Introduction Angiotensin-converting enzyme 2 (ACE2) is a member of the renin–angiotensin system (RAS) that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7).1,2 ACE2 is thought to function as a negative regulator of the RAS by degrading Ang II and producing Ang-(1-7) to counterbalance the Ang II-forming activity of ACE. Although ACE2 is reported to localize in renal glomeruli and tubules,3–6 the differences in ACE2 expression within the kidney seem to be not only tissue-specific but also cell-specific.6–9 Glomerular expression of ACE2 is reduced in diabetic mice,6 and reduced ACE2 gene and protein expression has been confirmed in renal biopsies of patients with type 2 diabetes.7 On the other hand, at the tubular level, increased ACE2 activity and protein expression have been found in diabetic mice.8,9 The renal RAS, specifically Ang II, plays a pivotal role in the pathogenesis
of diabetic nephropathy.10 Ang II and ACE are activated in type 2 diabetes11 and are involved in the development of microvascular and macrovascular complications of diabetes such as nephropathy, retinopathy, and cardiovascular disease.12 ACE 2 plays an integral role in protecting against
1Division
of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 2Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan Corresponding author: Masanori Abe, Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi Kami-chou, Itabashi-ku, Tokyo 173-8610, Japan. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm). Downloaded from jra.sagepub.com at USD & Wegner Health Science Information Center on March 15, 2015
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Journal of the Renin-Angiotensin-Aldosterone System 16(1)
renal damage and cardiovascular disease.8,13 It was reported that deletion of ACE2 leads to the development of Ang II-dependent renal damage, suggesting ACE2 as a renoprotective target in diabetes.14 ACE2 is a homologue of ACE but is not blocked by ACE inhibitors. However, there are no clinical data showing whether Ang II type 1 receptor blockers (ARB) increase ACE2 activity. In this study, we evaluated the changes in urinary ACE2 levels resulting from ARB treatment in diabetes patients with chronic kidney disease (CKD).
Research design and methods This prospective, open-label, interventional study was conducted with 31 outpatients after obtaining written informed consent and with the approval of the local ethics committee. The study was performed in accordance with the Declaration of Helsinki. Enrollment criteria were as follows: 1) type 2 diabetes with nephropathy under stable glycemic control, defined as a hemoglobin A1c (HbA1c) level 30 mg/g (average of two consecutive measurements recorded during the 8-week pre-treatment period); 3) estimated glomerular filtration rate (eGFR) of 30–89 mL/min/1.73 m2; and 4) hypertension: systolic and diastolic blood pressure (BP) ≥130/80 mmHg treated with a fixed dose of antihypertensive agents other than RAS inhibitors for at least 8 weeks before the study. Exclusion criteria were as follows: 1) age 80 years; 2) more than second-degree hypertension (BP >160/100 mmHg)15; 3) eGFR ≥90 mL/min/1.73 m2 or
research-article2014
JRA0010.1177/1470320314551443Journal of the Renin-Angiotensin-Aldosterone SystemAbe et al.
Original Article
Urinary angiotensin-converting enzyme 2 increases in diabetic nephropathy by angiotensin II type 1 receptor blocker olmesartan
Journal of the Renin-AngiotensinAldosterone System 2015, Vol. 16(1) 159–164 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320314551443 jra.sagepub.com
Masanori Abe1, Osamu Oikawa1, Kazuyoshi Okada1 and Masayoshi Soma1,2
Abstract Introduction: Angiotensin-converting enzyme 2 (ACE2) is a member of the renin–angiotensin system that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7). We evaluated the changes in urinary ACE2 levels in response to treatment with the angiotensin II type 1 receptor blocker olmesartan in diabetes patients with nephropathy. Materials and methods: This prospective, open-label, interventional study was conducted with 31 type 2 diabetes patients with nephropathy. After initial evaluation, patients received 20 mg/day olmesartan, which was increased to 40 mg/day over a 24-week period. Results: In diabetes patients with chronic kidney disease, olmesartan significantly increased urinary ACE2 levels independently of blood pressure and plasma aldosterone levels and reduced albuminuria, urinary liver-type fatty acid binding protein (L-FABP), and plasma aldosterone levels. Multivariable regression analysis revealed that the change in urinary L-FABP levels was an independent predictor of increased urinary ACE2 levels. Conclusion: Olmesartan may have the unique effect of increasing urinary ACE2 levels. However, whether this contributes to olmesartan’s renoprotective effect must be examined further. Keywords Angiotensin-converting enzyme 2, angiotensin II type 1 receptor blocker, chronic kidney disease, diabetic nephropathy, olmesartan Date received: 30 April 2014; accepted: 17 August 2014
Introduction Angiotensin-converting enzyme 2 (ACE2) is a member of the renin–angiotensin system (RAS) that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7).1,2 ACE2 is thought to function as a negative regulator of the RAS by degrading Ang II and producing Ang-(1-7) to counterbalance the Ang II-forming activity of ACE. Although ACE2 is reported to localize in renal glomeruli and tubules,3–6 the differences in ACE2 expression within the kidney seem to be not only tissue-specific but also cell-specific.6–9 Glomerular expression of ACE2 is reduced in diabetic mice,6 and reduced ACE2 gene and protein expression has been confirmed in renal biopsies of patients with type 2 diabetes.7 On the other hand, at the tubular level, increased ACE2 activity and protein expression have been found in diabetic mice.8,9 The renal RAS, specifically Ang II, plays a pivotal role in the pathogenesis
of diabetic nephropathy.10 Ang II and ACE are activated in type 2 diabetes11 and are involved in the development of microvascular and macrovascular complications of diabetes such as nephropathy, retinopathy, and cardiovascular disease.12 ACE 2 plays an integral role in protecting against
1Division
of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 2Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan Corresponding author: Masanori Abe, Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi Kami-chou, Itabashi-ku, Tokyo 173-8610, Japan. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm). Downloaded from jra.sagepub.com at USD & Wegner Health Science Information Center on March 15, 2015
160
Journal of the Renin-Angiotensin-Aldosterone System 16(1)
renal damage and cardiovascular disease.8,13 It was reported that deletion of ACE2 leads to the development of Ang II-dependent renal damage, suggesting ACE2 as a renoprotective target in diabetes.14 ACE2 is a homologue of ACE but is not blocked by ACE inhibitors. However, there are no clinical data showing whether Ang II type 1 receptor blockers (ARB) increase ACE2 activity. In this study, we evaluated the changes in urinary ACE2 levels resulting from ARB treatment in diabetes patients with chronic kidney disease (CKD).
Research design and methods This prospective, open-label, interventional study was conducted with 31 outpatients after obtaining written informed consent and with the approval of the local ethics committee. The study was performed in accordance with the Declaration of Helsinki. Enrollment criteria were as follows: 1) type 2 diabetes with nephropathy under stable glycemic control, defined as a hemoglobin A1c (HbA1c) level 30 mg/g (average of two consecutive measurements recorded during the 8-week pre-treatment period); 3) estimated glomerular filtration rate (eGFR) of 30–89 mL/min/1.73 m2; and 4) hypertension: systolic and diastolic blood pressure (BP) ≥130/80 mmHg treated with a fixed dose of antihypertensive agents other than RAS inhibitors for at least 8 weeks before the study. Exclusion criteria were as follows: 1) age 80 years; 2) more than second-degree hypertension (BP >160/100 mmHg)15; 3) eGFR ≥90 mL/min/1.73 m2 or
