Myostatin in the Arterial Wall of Patients with End-Stage Renal Disease
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- Esposito Pasquale
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Ospedale Policlinico San Martino
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- Verzola Daniela
- Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Ospedale Policlinico San Martino
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- Porta Edoardo La
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Ospedale Policlinico San Martino
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- Milanesi Samantha
- Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Ospedale Policlinico San Martino
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- Grignano Maria Antonietta
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia
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- Avella Alessandro
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia
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- Gregorini Marilena
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia
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- Abelli Massimo
- Service of Surgery, University of Pavia, Fondazione IRCCS Policlinico San Matteo
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- Ticozzelli Elena
- Service of Surgery, University of Pavia, Fondazione IRCCS Policlinico San Matteo
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- Rampino Teresa
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia
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- Garibotto Giacomo
- Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Ospedale Policlinico San Martino
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<p>Aim: Myostatin (Mstn) has been described as a trigger for the progression of atherosclerosis. In this study, we evaluated the role of Mstn in arterial remodeling in patients with end-stage renal disease (ESRD). </p><p>Methods: Vascular specimens were collected from 16 ESRD patients (56.4±7.9 years) undergoing renal transplant (recipients) and 15 deceased kidney non-uremic donors (55.4±12.1 years). We studied gene and protein expression of Mstn, ubiquitin ligases, Atrogin-1, and muscle ring finger protein-1 (MuRF-1), inflammatory marker CCL2, cytoskeleton components, and Klotho by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Moreover, we assessed vascular calcification and collagen deposition. Finally, we studied the effects of recombinant Mstn on rat vascular smooth muscle cells (VSMCs, A7r5) and evaluated the effects of uremic serum (US) on primary human VSMCs.</p><p>Results: Myostatin mRNA was upregulated in the arterial vascular wall of recipients compared with donors (~15- folds, p＜0.05). This response was accompanied by the upregulation of gene expression of Atrogin-1 and MuRF-1 (＋2.5- and ＋10-fold) and CCL2 (＋3-fold). Conversely, we found downregulation of protein expression of Smoothelin, α-smooth muscle actin (α-SMA), vimentin, and Klotho (-85%, -50%, -70%, and -80%, respectively; p＜0.05) and gene expression of vimentin and Klotho. Exposition of A7r5 to Mstn induced a time-dependent SMAD 2/SMAD 3 phosphorylation and expression of collagen-1 and transforming growth factor β (TGFβ) mRNA, while US induced overexpression of Mstn and Atrogin-1 and downregulation of Smoothelin and Klotho. </p><p>Conclusions: Our data suggest that uremia might induce vascular Mstn gene expression together with a complex pathway of molecular and structural changes in the vascular wall. Myostatin, in turn, can translate the metabolic alterations of uremia into profibrotic and stiffness inducing signals.</p>
収録刊行物
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- Ｊｏｕｒｎａｌ ｏｆ Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ ａｎｄ Ｔｈｒｏｍｂｏｓｉｓ
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Ｊｏｕｒｎａｌ ｏｆ Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ ａｎｄ Ｔｈｒｏｍｂｏｓｉｓ 27 (10), 1039-1052, 2020-10-01
一般社団法人 日本動脈硬化学会