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Bódi B, Vágó RR, Nagy L, Ráduly AP, Gulyás A, Kupecz K, Azar L, Márványkövi FM, Szűcs G, Siska A, Cserni G, Földesi I, Papp Z, Sárközy M. Differential Myocardial Responses in Male and Female Rats with Uremic Cardiomyopathy. Int J Mol Sci 2025; 26:2259. [PMID: 40076880 PMCID: PMC11900185 DOI: 10.3390/ijms26052259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/24/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Uremic cardiomyopathy, characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis, is a common cardiovascular complication of chronic kidney disease (CKD). Men are at a higher risk for cardiovascular and renal diseases, compared to age-matched, pre-menopausal women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy through the characterization of functional and molecular indices of myocardial remodeling in a rat model. CKD was induced by a 5/6 nephrectomy in 9-week-old male and female Wistar rats. Serum and urine tests, transthoracic echocardiography, left ventricular (LV) histology, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed at week 8 or 9. Moreover, LV alterations were also tested in permeabilized cardiomyocytes (CMs) by force measurements and Western immunoblotting. CKD resulted in the development of a more severe uremic cardiomyopathy in male rats-including LVH, LV diastolic dysfunction, and fibrosis-than in female rats, where only LVH was observed. A uremic cardiomyopathy was also associated with a decrease in maximal Ca2+-activated force (Fmax) in CMs of male rats. Additionally, increases in CM Ca2+-independent passive stiffness (Fpassive) and decreases in cardiac myosin-binding protein C (cMyBP-C) phosphorylation levels were significantly larger in male than female rats. In conclusion, a uremic cardiomyopathy involved cardiac remodeling in both sexes. Nevertheless, male rats exhibited more pronounced signs of macroscopic and microscopic alterations than their female counterparts, illustrating a sex-dependent component of uremic cardiomyopathy.
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Affiliation(s)
- Beáta Bódi
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (R.R.V.); (L.N.); (A.P.R.); (Z.P.)
| | - Rebeka Rita Vágó
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (R.R.V.); (L.N.); (A.P.R.); (Z.P.)
| | - László Nagy
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (R.R.V.); (L.N.); (A.P.R.); (Z.P.)
- Department of Cardiology, Division of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Arnold Péter Ráduly
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (R.R.V.); (L.N.); (A.P.R.); (Z.P.)
- Department of Cardiology, Division of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - András Gulyás
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (A.G.); (K.K.); (L.A.)
| | - Klaudia Kupecz
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (A.G.); (K.K.); (L.A.)
| | - Lilian Azar
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (A.G.); (K.K.); (L.A.)
| | - Fanni Magdolna Márványkövi
- Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (F.M.M.); (G.S.)
| | - Gergő Szűcs
- Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (F.M.M.); (G.S.)
| | - Andrea Siska
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (A.S.); (I.F.)
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary;
| | - Imre Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (A.S.); (I.F.)
| | - Zoltán Papp
- Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (R.R.V.); (L.N.); (A.P.R.); (Z.P.)
| | - Márta Sárközy
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (A.G.); (K.K.); (L.A.)
- Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary; (F.M.M.); (G.S.)
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Sarker M, Chowdhury N, Bristy AT, Emran T, Karim R, Ahmed R, Shaki MM, Sharkar SM, Sayedur Rahman GM, Reza HM. Astaxanthin protects fludrocortisone acetate-induced cardiac injury by attenuating oxidative stress, fibrosis, and inflammation through TGF-β/Smad signaling pathway. Biomed Pharmacother 2024; 181:117703. [PMID: 39586138 DOI: 10.1016/j.biopha.2024.117703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/05/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024] Open
Abstract
Hypertensive rats serve as a good experimental model for studying the pathophysiology of cardiac hypertrophy and remodeling leading to heart failure. In this study, we aimed to analyze the effect of astaxanthin and possible mechanisms involved in alleviating oxidative stress, fibrosis and inflammation that triggers cardiac remodeling using male uninephrectomized Long Evans rats. Cardiac hypertrophy and hypertension were induced in rats termed as 'FCA-Salt rats' by an oral administration of fludrocortisone acetate (FCA) and 1 % NaCl in drinking water. Biochemical assays showed that FCA-Salt rats exhibited an upregulation of oxidative stress markers AOPP, MDA and downregulation of NO in heart and kidney, which was reversed by astaxanthin treatment. Astaxanthin further regularized the reduced activities of antioxidant enzymes GSH, SOD and CAT in these tissues. ELISA revealed that astaxanthin significantly reduced the inflammatory response by reducing the elevated levels of IL-1β, IL-17a, and TNF-α and pro-fibrotic marker TGF-β1 in plasma. Real-time qPCR depicted an upregulation of TNF-α, IL-1β, IL-6, IL-17A as well as signaling molecules TGF-β1, Smad2 and Smad3 in heart of FCA-Salt rats, which was reduced significantly by astaxanthin. Sirius red staining showed that the cardiac and renal fibrosis was significantly improved by astaxanthin treatment. Together, our results suggest that astaxanthin treatment is beneficial in protecting cardio-renal damage in hypertension through TGF-β/Smad signaling pathway, hence, this molecule may be considered for the maintenance of cardio-renal health.
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Affiliation(s)
- Manoneeta Sarker
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Nowreen Chowdhury
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Anika Tabassum Bristy
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Tushar Emran
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Reatul Karim
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Rezwana Ahmed
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md Mostaid Shaki
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Shazid Md Sharkar
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - G M Sayedur Rahman
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Hasan Mahmud Reza
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh.
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Kundu S, Gairola S, Verma S, Mugale MN, Sahu BD. Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling. Basic Res Cardiol 2024; 119:831-852. [PMID: 38771318 DOI: 10.1007/s00395-024-01056-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 05/11/2024] [Accepted: 05/11/2024] [Indexed: 05/22/2024]
Abstract
Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.
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Affiliation(s)
- Sourav Kundu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, 781101, India
| | - Shobhit Gairola
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, 781101, India
| | - Smriti Verma
- Department of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Madhav Nilakanth Mugale
- Department of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Bidya Dhar Sahu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, 781101, India.
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Dinh H, Kovács ZZA, Kis M, Kupecz K, Sejben A, Szűcs G, Márványkövi F, Siska A, Freiwan M, Pósa SP, Galla Z, Ibos KE, Bodnár É, Lauber GY, Goncalves AIA, Acar E, Kriston A, Kovács F, Horváth P, Bozsó Z, Tóth G, Földesi I, Monostori P, Cserni G, Podesser BK, Lehoczki A, Pokreisz P, Kiss A, Dux L, Csabafi K, Sárközy M. Role of the kisspeptin-KISS1R axis in the pathogenesis of chronic kidney disease and uremic cardiomyopathy. GeroScience 2024; 46:2463-2488. [PMID: 37987885 PMCID: PMC10828495 DOI: 10.1007/s11357-023-01017-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.
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Affiliation(s)
- Hoa Dinh
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
- Department of Biochemistry, Bach Mai Hospital, Hanoi, 100000, Vietnam
| | - Zsuzsanna Z A Kovács
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Merse Kis
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Klaudia Kupecz
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Anita Sejben
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Gergő Szűcs
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Fanni Márványkövi
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Andrea Siska
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Marah Freiwan
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Szonja Polett Pósa
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Zsolt Galla
- Metabolic and Newborn Screening Laboratory, Department of Pediatrics, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Katalin Eszter Ibos
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Éva Bodnár
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Gülsüm Yilmaz Lauber
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - Ana Isabel Antunes Goncalves
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - Eylem Acar
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - András Kriston
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, 6726, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Ferenc Kovács
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, 6726, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Péter Horváth
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, 6726, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Zsolt Bozsó
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Gábor Tóth
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Péter Monostori
- Metabolic and Newborn Screening Laboratory, Department of Pediatrics, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - Andrea Lehoczki
- Departments of Hematology and Stem Cell Transplantation, South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Saint Ladislaus Campus, Budapest, Hungary
| | - Peter Pokreisz
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - László Dux
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary.
| | - Krisztina Csabafi
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Márta Sárközy
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary.
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary.
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Carresi C, Cardamone A, Coppoletta AR, Caminiti R, Macrì R, Lorenzo F, Scarano F, Mollace R, Guarnieri L, Ruga S, Nucera S, Musolino V, Gliozzi M, Palma E, Muscoli C, Volterrani M, Mollace V. The protective effect of Bergamot Polyphenolic Fraction on reno-cardiac damage induced by DOCA-salt and unilateral renal artery ligation in rats. Biomed Pharmacother 2024; 171:116082. [PMID: 38242036 DOI: 10.1016/j.biopha.2023.116082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/28/2023] [Accepted: 12/26/2023] [Indexed: 01/21/2024] Open
Abstract
To date, the complex pathological interactions between renal and cardiovascular systems represent a real global epidemic in both developed and developing countries. In this context, renovascular hypertension (RVH) remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation. Adult male Wistar rats underwent unilateral renal artery ligation and treatment with deoxycorticosterone acetate (DOCA) (20 mg/kg, s.c.), twice a week for a period of 4 weeks, and 1% sodium chloride (NaCl) water (n = 10). A subgroup of hypertensive rats received BPF (100 mg/kg/day for 28 consecutive days, n = 10) by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (that served as control, n = 8). Unilateral renal artery ligation followed by treatment with DOCA and 1% NaCl water resulted in a significant increase in mean arterial blood pressure (MAP; p< 0.05. vs CTRL) which strongly increased the resistive index (RI; p<0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p<0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion when compared to CTRL group, as shown by the increased time-to-peak (T2P; p<0.05) and the decreased whole peak capacity (Pk; p<0.01) in displacement and strain rate (p<0.05, respectively) in longitudinal motion. Consequently, the hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) when compared to CTRL group (p<0.05 in displacement and p <0.01 in strain rate). Furthermore, a significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p< 0.05 for IL-12(40), p< 0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p< 0.001) was observed compared to CTRL group. Interestingly, this pathological condition is prevented by BPF treatment. In particular, BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats (p< 0.05) and exerts a protective effect on the volume of the contralateral kidney (p <0.01). Moreover, BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p <0.01) and reducing the T2P in strain rate motion (p<0.05). These latter effects significantly improve MOWD (p <0.05) preventing the overt dyssynchrony in cardiac wall motion. Finally, the reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of some pro-inflammatory cytokines and chemokines (p<0.05 for KC and IL-12(40), p<0.01 for GM-CSF, IL-13, and TNF- α) restoring physiological levels of renal neutrophil gelatinase-associated lipocalin (NGAL, p<0.05) protein of the tethered kidney. In conclusion, the present results show, for the first time, that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage. Overall, these data point to a potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome.
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Affiliation(s)
- Cristina Carresi
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.
| | - Antonio Cardamone
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Anna Rita Coppoletta
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Rosamaria Caminiti
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Roberta Macrì
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Lorenzo
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Federica Scarano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Rocco Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Italy
| | - Lorenza Guarnieri
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Stefano Ruga
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Saverio Nucera
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Musolino
- Laboratory of Pharmaceutical Biology, Department of Health Sciences, Institute of Research for Food Safety & Health IRC-FSH, University "Magna Græcia" of Catanzaro, 88100 Catanzaro, Italy
| | - Micaela Gliozzi
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Carolina Muscoli
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | | | - Vincenzo Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
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Chien MJ, Li SJ, Wong SC, Chiang CH, Lin YY, Mersmann HJ, Chen CY. Determination of mitochondrial functions and damage in kidney in female LeeSung minipigs with a high-fat diet-induced obesity. Arch Physiol Biochem 2023; 129:1289-1297. [PMID: 34338085 DOI: 10.1080/13813455.2021.1949022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/23/2021] [Indexed: 10/20/2022]
Abstract
The purpose of this study was to investigate the nexus between mitochondrial function and kidney injury by using a dietary-induced obese minipig model. Female Lee-Sung minipigs feeding a high-fat diet (HFD) for 6 months exhibited obesity, hyperglycaemia and dyslipidemia. HFD elevated the levels of plasma biomarkers related to renal injury, including symmetric dimethylarginine, creatinine and urea nitrogen. An extensive structural change in tubules and glomeruli was observed in HFD-fed pigs. A great amount of triacylglycerol was accumulated in HFD kidney compared to control kidney, whereas a reduction of ATP level and antioxidant capacity were exhibited in HFD kidney. Moreover, HFD altered the expressions of mitochondrial-related protein in renal cortex. To conclude, long-term HFD feeding to Lee-Sung minipigs induced obesity and kidney injury accompanied by abnormal mitochondrial functions in the renal cortex, suggesting an interrelationship with renal disease progression.
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Affiliation(s)
- Miao-Ju Chien
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Sin-Jin Li
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Shiu-Chung Wong
- National Taiwan University Veterinary Hospital, National Taiwan University, Taipei, Taiwan
| | - Chun-Hsien Chiang
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Yuan-Yu Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Harry J Mersmann
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Ching-Yi Chen
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
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7
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Junho CVC, Frisch J, Soppert J, Wollenhaupt J, Noels H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin Kidney J 2023; 16:1786-1803. [PMID: 37915935 PMCID: PMC10616472 DOI: 10.1093/ckj/sfad085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 11/03/2023] Open
Abstract
The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both "single hit" as well as "multifactorial hit" models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.
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Affiliation(s)
| | - Janina Frisch
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
| | - Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Wollenhaupt
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
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8
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Sárközy M, Watzinger S, Kovács ZZ, Acar E, Márványkövi F, Szűcs G, Lauber GY, Galla Z, Siska A, Földesi I, Fintha A, Kriston A, Kovács F, Horváth P, Kővári B, Cserni G, Krenács T, Szabó PL, Szabó GT, Monostori P, Zins K, Abraham D, Csont T, Pokreisz P, Podesser BK, Kiss A. Neuregulin-1β Improves Uremic Cardiomyopathy and Renal Dysfunction in Rats. JACC Basic Transl Sci 2023; 8:1160-1176. [PMID: 37791301 PMCID: PMC10543921 DOI: 10.1016/j.jacbts.2023.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/01/2023] [Accepted: 03/01/2023] [Indexed: 10/05/2023]
Abstract
Chronic kidney disease is a global health problem affecting 10% to 12% of the population. Uremic cardiomyopathy is often characterized by left ventricular hypertrophy, fibrosis, and diastolic dysfunction. Dysregulation of neuregulin-1β signaling in the heart is a known contributor to heart failure. The systemically administered recombinant human neuregulin-1β for 10 days in our 5/6 nephrectomy-induced model of chronic kidney disease alleviated the progression of uremic cardiomyopathy and kidney dysfunction in type 4 cardiorenal syndrome. The currently presented positive preclinical data warrant clinical studies to confirm the beneficial effects of recombinant human neuregulin-1β in patients with chronic kidney disease.
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Affiliation(s)
- Márta Sárközy
- MEDICS Research Group, Department of Biochemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Interdisciplinary Center of Excellence, University of Szeged, Szeged, Hungary
| | - Simon Watzinger
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Zsuzsanna Z.A. Kovács
- MEDICS Research Group, Department of Biochemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Interdisciplinary Center of Excellence, University of Szeged, Szeged, Hungary
| | - Eylem Acar
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Fanni Márványkövi
- MEDICS Research Group, Department of Biochemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Interdisciplinary Center of Excellence, University of Szeged, Szeged, Hungary
| | - Gergő Szűcs
- MEDICS Research Group, Department of Biochemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Interdisciplinary Center of Excellence, University of Szeged, Szeged, Hungary
| | - Gülsüm Yilmaz Lauber
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Zsolt Galla
- Metabolic and Newborn Screening Laboratory, Department of Pediatrics, Albert Szent-Györgyi Medical School, University of Szeged, Hungary
| | - Andrea Siska
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Attila Fintha
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - András Kriston
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Ferenc Kovács
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Péter Horváth
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Bence Kővári
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tibor Krenács
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Petra Lujza Szabó
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Gábor Tamás Szabó
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Péter Monostori
- Metabolic and Newborn Screening Laboratory, Department of Pediatrics, Albert Szent-Györgyi Medical School, University of Szeged, Hungary
| | - Karin Zins
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Dietmar Abraham
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Tamás Csont
- MEDICS Research Group, Department of Biochemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Interdisciplinary Center of Excellence, University of Szeged, Szeged, Hungary
| | - Peter Pokreisz
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Bruno K. Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria
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9
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Dinh H, Kovács ZZA, Márványkövi F, Kis M, Kupecz K, Szűcs G, Freiwan M, Lauber GY, Acar E, Siska A, Ibos KE, Bodnár É, Kriston A, Kovács F, Horváth P, Földesi I, Cserni G, Podesser BK, Pokreisz P, Kiss A, Dux L, Csabafi K, Sárközy M. The kisspeptin-1 receptor antagonist peptide-234 aggravates uremic cardiomyopathy in a rat model. Sci Rep 2023; 13:14046. [PMID: 37640761 PMCID: PMC10462750 DOI: 10.1038/s41598-023-41037-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023] Open
Abstract
Uremic cardiomyopathy is characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis. Dysregulation of the kisspeptin receptor (KISS1R)-mediated pathways are associated with the development of fibrosis in cancerous diseases. Here, we investigated the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (i) Sham, (ii) chronic kidney disease (CKD) induced by 5/6 nephrectomy, (iii) CKD treated with a lower dose of P234 (ip. 13 µg/day), (iv) CKD treated with a higher dose of P234 (ip. 26 µg/day). Treatments were administered daily from week 3 for 10 days. At week 13, the P234 administration did not influence the creatinine clearance and urinary protein excretion. However, the higher dose of P234 led to reduced anterior and posterior wall thicknesses, more severe interstitial fibrosis, and overexpression of genes associated with left ventricular remodeling (Ctgf, Tgfb, Col3a1, Mmp9), stretch (Nppa), and apoptosis (Bax, Bcl2, Casp7) compared to the CKD group. In contrast, no significant differences were found in the expressions of apoptosis-associated proteins between the groups. Our results suggest that the higher dose of P234 hastens the development and pathophysiology of uremic cardiomyopathy by activating the fibrotic TGF-β-mediated pathways.
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Affiliation(s)
- Hoa Dinh
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
- Department of Biochemistry, Bach Mai Hospital, Hanoi, 100000, Vietnam
| | - Zsuzsanna Z A Kovács
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Fanni Márványkövi
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Merse Kis
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Klaudia Kupecz
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Gergő Szűcs
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Marah Freiwan
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Gülsüm Yilmaz Lauber
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, A1090, Vienna, Austria
| | - Eylem Acar
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, A1090, Vienna, Austria
| | - Andrea Siska
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Katalin Eszter Ibos
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Éva Bodnár
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - András Kriston
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, 6726, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Ferenc Kovács
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, 6726, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Péter Horváth
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, 6726, Szeged, Hungary
- Single-Cell Technologies Ltd, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Imre Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, A1090, Vienna, Austria
| | - Peter Pokreisz
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, A1090, Vienna, Austria
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research and Translational Surgery, Medical University of Vienna, A1090, Vienna, Austria
| | - László Dux
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary.
| | - Krisztina Csabafi
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary
| | - Márta Sárközy
- Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary.
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6720, Hungary.
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10
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Nguyen IT, Joles JA, Verhaar MC, Lamb HJ, Dekkers IA. Obesity in relation to cardiorenal function. VISCERAL AND ECTOPIC FAT 2023:243-264. [DOI: 10.1016/b978-0-12-822186-0.00006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Dargam V, Ng HH, Nasim S, Chaparro D, Irion CI, Seshadri SR, Barreto A, Danziger ZC, Shehadeh LA, Hutcheson JD. S2 Heart Sound Detects Aortic Valve Calcification Independent of Hemodynamic Changes in Mice. Front Cardiovasc Med 2022; 9:809301. [PMID: 35694672 PMCID: PMC9174427 DOI: 10.3389/fcvm.2022.809301] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 03/18/2022] [Indexed: 11/16/2022] Open
Abstract
Background Calcific aortic valve disease (CAVD) is often undiagnosed in asymptomatic patients, especially in underserved populations. Although artificial intelligence has improved murmur detection in auscultation exams, murmur manifestation depends on hemodynamic factors that can be independent of aortic valve (AoV) calcium load and function. The aim of this study was to determine if the presence of AoV calcification directly influences the S2 heart sound. Methods Adult C57BL/6J mice were assigned to the following 12-week-long diets: (1) Control group (n = 11) fed a normal chow, (2) Adenine group (n = 4) fed an adenine-supplemented diet to induce chronic kidney disease (CKD), and (3) Adenine + HP (n = 9) group fed the CKD diet for 6 weeks, then supplemented with high phosphate (HP) for another 6 weeks to induce AoV calcification. Phonocardiograms, echocardiogram-based valvular function, and AoV calcification were assessed at endpoint. Results Mice on the Adenine + HP diet had detectable AoV calcification (9.28 ± 0.74% by volume). After segmentation and dimensionality reduction, S2 sounds were labeled based on the presence of disease: Healthy, CKD, or CKD + CAVD. The dataset (2,516 S2 sounds) was split subject-wise, and an ensemble learning-based algorithm was developed to classify S2 sound features. For external validation, the areas under the receiver operating characteristic curve of the algorithm to classify mice were 0.9940 for Healthy, 0.9717 for CKD, and 0.9593 for CKD + CAVD. The algorithm had a low misclassification performance of testing set S2 sounds (1.27% false positive, 1.99% false negative). Conclusion Our ensemble learning-based algorithm demonstrated the feasibility of using the S2 sound to detect the presence of AoV calcification. The S2 sound can be used as a marker to identify AoV calcification independent of hemodynamic changes observed in echocardiography.
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Affiliation(s)
- Valentina Dargam
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
| | - Hooi Hooi Ng
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
- Department of Human and Molecular Genetics, Florida International University, Miami, FL, United States
| | - Sana Nasim
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
| | - Daniel Chaparro
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
| | - Camila Iansen Irion
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Coral Gables, FL, United States
| | - Suhas Rathna Seshadri
- Department of Medical Education, University of Miami Miller School of Medicine, Coral Gables, FL, United States
| | - Armando Barreto
- Department of Electrical and Computer Engineering, Florida International University, Miami, FL, United States
| | - Zachary C. Danziger
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
| | - Lina A. Shehadeh
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Coral Gables, FL, United States
- Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Coral Gables, FL, United States
| | - Joshua D. Hutcheson
- Department of Biomedical Engineering, Florida International University, Miami, FL, United States
- Biomolecular Sciences Institute, Florida International University, Miami, FL, United States
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12
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Gutsol AA, Blanco P, Hale TM, Thibodeau JF, Holterman CE, Nasrallah R, Correa JWN, Afanasiev SA, Touyz RM, Kennedy CRJ, Burger D, Hébert RL, Burns KD. Comparative analysis of hypertensive nephrosclerosis in animal models of hypertension and its relevance to human pathology. Glomerulopathy. PLoS One 2022; 17:e0264136. [PMID: 35176122 PMCID: PMC8853553 DOI: 10.1371/journal.pone.0264136] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 02/03/2022] [Indexed: 01/09/2023] Open
Abstract
Current research on hypertension utilizes more than fifty animal models that rely mainly on stable increases in systolic blood pressure. In experimental hypertension, grading or scoring of glomerulopathy in the majority of studies is based on a wide range of opinion-based histological changes that do not necessarily comply with lesional descriptors for glomerular injury that are well-established in clinical pathology. Here, we provide a critical appraisal of experimental hypertensive glomerulopathy with the same approach used to assess hypertensive glomerulopathy in humans. Four hypertensive models with varying pathogenesis were analyzed–chronic angiotensin II infused mice, mice expressing active human renin in the liver (TTRhRen), spontaneously hypertensive rats (SHR), and Goldblatt two-kidney one-clip rats (2K1C). Analysis of glomerulopathy utilized the same criteria applied in humans–hyalinosis, focal segmental glomerulosclerosis (FSGS), ischemic, hypertrophic and solidified glomeruli, or global glomerulosclerosis (GGS). Data from animal models were compared to human reference values. Kidneys in TTRhRen mice, SHR and the nonclipped kidneys in 2K1C rats had no sign of hyalinosis, FSGS or GGS. Glomerulopathy in these groups was limited to variations in mesangial and capillary compartment volumes, with mild increases in collagen deposition. Histopathology in angiotensin II infused mice corresponded to mesangioproliferative glomerulonephritis, but not hypertensive glomerulosclerosis. The number of nephrons was significantly reduced in TTRhRen mice and SHR, but did not correlate with severity of glomerulopathy. The most substantial human-like glomerulosclerotic lesions, including FSGS, ischemic obsolescent glomeruli and GGS, were found in the clipped kidneys of 2K1C rats. The comparison of affected kidneys to healthy control in animals produces lesion values that are numerically impressive but correspond to mild damage if compared to humans. Animal studies should be standardized by employing the criteria and classifications established in human pathology to make experimental and human data fully comparable for comprehensive analysis and model improvements.
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Affiliation(s)
- Alex A. Gutsol
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
- * E-mail:
| | - Paula Blanco
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Taben M. Hale
- Basic Medical Sciences Faculty, University of Arizona, Tucson, AZ, United States of America
| | - Jean-Francois Thibodeau
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
| | - Chet E. Holterman
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
| | - Rania Nasrallah
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
| | - Jose W. N. Correa
- Department of Physiological Sciences, Biological Sciences Institute, Federal University of Amazonas, Manaus, Brazil
| | | | - Rhian M. Touyz
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Chris R. J. Kennedy
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Dylan Burger
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Richard L. Hébert
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Kevin D. Burns
- Ottawa Hospital Research Institute & Kidney Research Centre, University of Ottawa, Ottawa, ON, Canada
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
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13
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Wang J, Lin Y, Chen X, Liu Y, Zhou T. Mesenchymal stem cells: A new therapeutic tool for chronic kidney disease. Front Cell Dev Biol 2022; 10:910592. [PMID: 36268508 PMCID: PMC9577598 DOI: 10.3389/fcell.2022.910592] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 09/12/2022] [Indexed: 02/05/2023] Open
Abstract
Chronic kidney disease (CKD) has a major impact on public health, which could progress to end-stage kidney disease (ESRD) and consume many medical resources. Currently, the treatment for CKD has many flaws, so more effective treatment tools are urgently required for CKD. Mesenchymal stem cells (MSCs) are primitive cells with self-renewal and proliferation capacity and differentiation potential. Extensive preclinical and clinical data has shown that cell-based therapies using MSCs can modulate immunity, inhibit inflammatory factors, and improve renal function in CKD, suggesting that MSCs have the potential to be a new, effective therapeutic tool for CKD. In this review, we will describe different kinds of MSCs and MSCs products for the treatment of CKD in experimental models and clinical trials, potential signaling pathways, therapeutic efficacy, and critical issues that need to be addressed before therapeutic application in humans.
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Affiliation(s)
- Jiali Wang
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yongda Lin
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Xiutian Chen
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yiping Liu
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, Shantou, China
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14
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Ischemic preconditioning protects the heart against ischemia-reperfusion injury in chronic kidney disease in both males and females. Biol Sex Differ 2021; 12:49. [PMID: 34488888 PMCID: PMC8420010 DOI: 10.1186/s13293-021-00392-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Uremic cardiomyopathy is a common cardiovascular complication of chronic kidney disease (CKD) characterized by left ventricular hypertrophy (LVH) and fibrosis enhancing the susceptibility of the heart to acute myocardial infarction. In the early stages of CKD, approximately 60% of patients are women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning (IPRE) in experimental CKD. METHODS CKD was induced by 5/6 nephrectomy in 9-week-old male and female Wistar rats. Two months later, serum and urine laboratory parameters were measured to verify the development of CKD. Transthoracic echocardiography was performed to assess cardiac function and morphology. Cardiomyocyte hypertrophy and fibrosis were measured by histology. Left ventricular expression of A- and B-type natriuretic peptides (ANP and BNP) were measured by qRT-PCR and circulating BNP level was measured by ELISA. In a subgroup of animals, hearts were perfused according to Langendorff and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPRE (3 × 5 min I/R cycles applied before index ischemia). Then infarct size or phosphorylated and total forms of proteins related to the cardioprotective RISK (AKT, ERK1,2) and SAFE (STAT3) pathways were measured by Western blot. RESULTS The severity of CKD was similar in males and females. However, CKD males developed more severe LVH compared to females as assessed by echocardiography. Histology revealed cardiac fibrosis only in males in CKD. LV ANP expression was significantly increased due to CKD in both sexes, however, LV BNP and circulating BNP levels failed to significantly increase in CKD. In both sexes, IPRE significantly decreased the infarct size in both the sham-operated and CKD groups. IPRE significantly increased the phospho-STAT3/STAT3 ratio in sham-operated but not in CKD animals in both sexes. There were no significant differences in phospho-AKT/AKT and phospho-ERK1,2/ERK1,2 ratios between the groups. CONCLUSION The infarct size-limiting effect of IPRE was preserved in both sexes in CKD despite the more severe uremic cardiomyopathy in male CKD rats. Further research is needed to identify crucial molecular mechanisms in the cardioprotective effect of IPRE in CKD.
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Kovács ZZA, Szűcs G, Freiwan M, Kovács MG, Márványkövi FM, Dinh H, Siska A, Farkas K, Kovács F, Kriston A, Horváth P, Kővári B, Cserni BG, Cserni G, Földesi I, Csont T, Sárközy M. Comparison of the antiremodeling effects of losartan and mirabegron in a rat model of uremic cardiomyopathy. Sci Rep 2021; 11:17495. [PMID: 34471171 PMCID: PMC8410807 DOI: 10.1038/s41598-021-96815-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (β3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the β3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, β3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the β3-AR.
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Affiliation(s)
- Zsuzsanna Z A Kovács
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Gergő Szűcs
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Marah Freiwan
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Mónika G Kovács
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Fanni M Márványkövi
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Hoa Dinh
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary
| | - Andrea Siska
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6720, Hungary
| | - Katalin Farkas
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6720, Hungary
| | - Ferenc Kovács
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, Szeged, 6726, Hungary
- Single-Cell Technologies Ltd, Temesvári krt. 62, Szeged, 6726, Hungary
| | - András Kriston
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, Szeged, 6726, Hungary
- Single-Cell Technologies Ltd, Temesvári krt. 62, Szeged, 6726, Hungary
| | - Péter Horváth
- Synthetic and Systems Biology Unit, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, Szeged, 6726, Hungary
- Single-Cell Technologies Ltd, Temesvári krt. 62, Szeged, 6726, Hungary
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland
| | - Bence Kővári
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged, 6720, Hungary
| | - Bálint Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged, 6720, Hungary
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged, 6720, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, Szeged, 6720, Hungary
| | - Tamás Csont
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary.
| | - Márta Sárközy
- MEDICS Research Group, Department of Biochemistry, Interdisciplinary Center of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary.
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Wong CY. Current advances of stem cell-based therapy for kidney diseases. World J Stem Cells 2021; 13:914-933. [PMID: 34367484 PMCID: PMC8316868 DOI: 10.4252/wjsc.v13.i7.914] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/10/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients’ quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.
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Affiliation(s)
- Chee-Yin Wong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang 43000, Selangor, Malaysia
- Research Department, Cytopeutics, Cyberjaya 63000, Selangor, Malaysia
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17
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Prieto-Carrasco R, Silva-Palacios A, Rojas-Morales P, Aparicio-Trejo OE, Medina-Reyes EI, Hernández-Cruz EY, Sánchez-Garibay C, Salinas-Lara C, Pavón N, Roldán FJ, Zazueta C, Tapia E, Pedraza-Chaverri J. Unilateral Ureteral Obstruction for 28 Days in Rats Is Not Associated with Changes in Cardiac Function or Alterations in Mitochondrial Function. BIOLOGY 2021; 10:671. [PMID: 34356526 PMCID: PMC8301354 DOI: 10.3390/biology10070671] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/10/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022]
Abstract
Our work evaluated cardiac function and mitochondrial bioenergetics parameters in hearts from male Wistar rats subjected to the UUO model during 28 days of progression. We measured markers of kidney damage and inflammation in plasma and renal fibrosis by histological analysis and Western blot. Cardiac function was evaluated by echocardiography and proteins involved in cardiac damage by Western blot. Oxygen consumption and transmembrane potential were monitored in cardiac mitochondria using high-resolution respirometry. We also determined the activity of ATP synthase and antioxidant enzymes such as glutathione peroxidase, glutathione reductase, and catalase. Our results show that, although renal dysfunction is established in animals subjected to ureteral obstruction, cardiac function is maintained along with mitochondrial function and antioxidant enzymes activity after 28 days of injury evolution. Our results suggest that renocardiac syndrome might develop but belatedly in obstruction-induced renal damage, opening the opportunity for treatment to prevent this condition.
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Affiliation(s)
- Rodrigo Prieto-Carrasco
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico; (R.P.-C.); (P.R.-M.); (O.E.A.-T.); (E.I.M.-R.); (E.Y.H.-C.)
- Department of Cardio-Renal Pathophysiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - Alejandro Silva-Palacios
- Department of Cardiovascular Biomedicine, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (A.S.-P.); (C.Z.)
| | - Pedro Rojas-Morales
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico; (R.P.-C.); (P.R.-M.); (O.E.A.-T.); (E.I.M.-R.); (E.Y.H.-C.)
- Department of Cardio-Renal Pathophysiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - Omar Emiliano Aparicio-Trejo
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico; (R.P.-C.); (P.R.-M.); (O.E.A.-T.); (E.I.M.-R.); (E.Y.H.-C.)
| | - Estefany Ingrid Medina-Reyes
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico; (R.P.-C.); (P.R.-M.); (O.E.A.-T.); (E.I.M.-R.); (E.Y.H.-C.)
| | - Estefani Yaquelin Hernández-Cruz
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico; (R.P.-C.); (P.R.-M.); (O.E.A.-T.); (E.I.M.-R.); (E.Y.H.-C.)
| | - Carlos Sánchez-Garibay
- Department of Neuropathology, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez, Mexico City 14269, Mexico; (C.S.-G.); (C.S.-L.)
| | - Citlaltepetl Salinas-Lara
- Department of Neuropathology, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez, Mexico City 14269, Mexico; (C.S.-G.); (C.S.-L.)
| | - Natalia Pavón
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - Francisco Javier Roldán
- Department of External Consultation, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - Cecilia Zazueta
- Department of Cardiovascular Biomedicine, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (A.S.-P.); (C.Z.)
| | - Edilia Tapia
- Department of Cardio-Renal Pathophysiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - José Pedraza-Chaverri
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico; (R.P.-C.); (P.R.-M.); (O.E.A.-T.); (E.I.M.-R.); (E.Y.H.-C.)
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18
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Wesseling M, Mulder E, Brans MAD, Kapteijn DMC, Bulthuis M, Pasterkamp G, Verhaar MC, Danser AHJ, van Goor H, Joles JA, de Jager SCA. Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model. Front Pharmacol 2021; 12:614656. [PMID: 34211391 PMCID: PMC8239225 DOI: 10.3389/fphar.2021.614656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 05/14/2021] [Indexed: 11/23/2022] Open
Abstract
Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.
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Affiliation(s)
- Marian Wesseling
- Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.,Laboratory for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Eva Mulder
- Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Maike A D Brans
- Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Daniek M C Kapteijn
- Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Marian Bulthuis
- Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands
| | - Gerard Pasterkamp
- Laboratory for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Marianne C Verhaar
- Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
| | - A H Jan Danser
- Department of Pharmacology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Harry van Goor
- Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands
| | - Jaap A Joles
- Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
| | - Saskia C A de Jager
- Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.,Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
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19
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Kieswich JE, Chen J, Alliouachene S, Caton PW, McCafferty K, Thiemermann C, Yaqoob MM. Immunohistochemistry of Kidney a-SMA, Collagen 1, and Collagen 3, in A Novel Mouse Model of Reno-cardiac Syndrome. Bio Protoc 2020; 10:e3751. [PMID: 33659410 DOI: 10.21769/bioprotoc.3751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/24/2020] [Accepted: 02/27/2020] [Indexed: 11/02/2022] Open
Abstract
Cardiorenal syndrome defines a synergistic pathology of the heart and kidneys where failure of one organ causes failure in the other. The incidence of cardiovascular mortality caused by this syndrome, is 20 fold higher in the end stage renal disease (ESRD) population compared to the population as a whole thus necessitating the need for improved therapeutic strategies to combat reno-cardiac pathologies. Murine in vivo models play a major role in such research permitting precise genetic modification thus reducing miscellany, however presently there is no steadfast model of reno-cardiac syndrome in the most common genetically modified mouse strain, the C57BL/6 mouse. In this study we have modified an established model of chronic renal disease using adenine diet and extended the associated pathology achieving chronic renal failure and consequent reno-cardiac syndrome in the C57BL/6 mouse. Eight week-old male C57BL/6 mice were acclimatized for 7 days before administration of a 0.15% adenine diet or control diet for 20 weeks after which the experiment was terminated and blood, urine and organs were collected and analyzed biochemically and by immunohistochemistry. Administration of 0.15% adenine diet caused progressive renal failure resulting in a reno-cardiac syndrome confirmed by a significantly increased heart to body weight ratio (P < 0.0001). Blood biochemistry showed that adenine fed mice had significantly increased serum creatinine, urea (P < 0.0001), and a significantly reduced glomerular filtration rate (P < 0.05), while immunohistochemistry of the kidneys for α-SMA, collagen 1 and collagen 3 showed severe fibrosis. We present a novel regimen of adenine diet which induces both chronic kidney disease and reno-cardiac syndrome in the C57BL/6 mouse strain. The non-surgical nature of this model makes it highly reproducible compared to other models currently available.
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Affiliation(s)
- Julius E Kieswich
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Jianmin Chen
- Department of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Samira Alliouachene
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Paul W Caton
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, Hodgkin Building, Guy's Campus, London, UK
| | - Kieran McCafferty
- Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Christoph Thiemermann
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Muhammad M Yaqoob
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
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20
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Funahashi Y, Chowdhury S, Eiwaz MB, Hutchens MP. Acute Cardiorenal Syndrome: Models and Heart-Kidney Connectors. Nephron Clin Pract 2020; 144:629-633. [PMID: 32814315 DOI: 10.1159/000509353] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/10/2020] [Indexed: 11/19/2022] Open
Abstract
Cardiorenal syndrome type 1 (CRS-1) is an acute kidney injury (AKI) due to acute worsening of cardiac function. More than 20% of patients with acute heart failure develop AKI, and AKI predicts poor outcome. Although a number of potential pathways have been suggested as heart-kidney connectors which might drive the syndrome, there are significant barriers to investigation, such as a paucity of animal models, a lack of specific biomarkers, and an inconsistent temporal and causal relationship between changes in cardiac flow and development of renal dysfunction. Thus, mechanisms of heart-kidney interaction are still unclear, and there is no specific or effective therapy for CRS-1. This review, therefore, focuses on mitigating these challenges in the investigation of CRS-1. We review the available models and focus on mechanistic insights gained from those models. In particular, we focus on non-flow and endocrine mediators of CRS-1 such as heart-derived messengers which alter renal function and which may represent targetable pathways in this syndrome. As precise connectors of heart-kidney interaction remain unclear, the establishment of animal and relevant cell-culture models and further investigation are required.
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Affiliation(s)
- Yoshio Funahashi
- Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA,
| | - Sheuli Chowdhury
- Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Mahaba B Eiwaz
- Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Michael P Hutchens
- Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA.,Portland Veterans Affairs Medical Center, Operative Care Division, Portland, Oregon, USA
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21
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Abstract
Congestion (i.e., backward failure) is an important culprit mechanism driving disease progression in heart failure. Nevertheless, congestion remains often underappreciated and clinicians underestimate the importance of congestion on the pathophysiology of decompensation in heart failure. In patients, it is however difficult to study how isolated congestion contributes to organ dysfunction, since heart failure and chronic kidney disease very often coexist in the so-called cardiorenal syndrome. Here, we review the existing relevant and suitable backward heart failure animal models to induce congestion, induced in the left- (i.e., myocardial infarction, rapid ventricular pacing) or right-sided heart (i.e., aorta-caval shunt, mitral valve regurgitation, and monocrotaline), and more specific animal models of congestion, induced by saline infusion or inferior vena cava constriction. Next, we examine critically how representative they are for the clinical situation. After all, a relevant animal model of isolated congestion offers the unique possibility of studying the effects of congestion in heart failure and the cardiorenal syndrome, separately from forward failure (i.e., impaired cardiac output). In this respect, new treatment options can be discovered.
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22
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Leader CJ, Kelly DJ, Sammut IA, Wilkins GT, Walker RJ. Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat. Physiol Rep 2020; 8:e14448. [PMID: 32441493 PMCID: PMC7243196 DOI: 10.14814/phy2.14448] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/15/2020] [Accepted: 04/24/2020] [Indexed: 01/10/2023] Open
Abstract
Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole-3-carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis.
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Affiliation(s)
| | - Darren J. Kelly
- Department of MedicineUniversity of MelbourneMelbourneVICAustralia
| | - Ivan A. Sammut
- Department of PharmacologyUniversity of OtagoDunedinNew Zealand
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23
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Himmelsbach A, Ciliox C, Goettsch C. Cardiovascular Calcification in Chronic Kidney Disease-Therapeutic Opportunities. Toxins (Basel) 2020; 12:toxins12030181. [PMID: 32183352 PMCID: PMC7150985 DOI: 10.3390/toxins12030181] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 02/07/2023] Open
Abstract
Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the 'point of no return'. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.
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O'Sullivan J, Finnie SL, Teenan O, Cairns C, Boyd A, Bailey MA, Thomson A, Hughes J, Bénézech C, Conway BR, Denby L. Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction. Front Physiol 2019; 10:1365. [PMID: 31803059 PMCID: PMC6872545 DOI: 10.3389/fphys.2019.01365] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 10/14/2019] [Indexed: 12/25/2022] Open
Abstract
Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidities including cardiovascular disease (CVD). Traditionally, the subtotal nephrectomy (remnant kidney) experimental model has been performed in rats to model progressive renal disease. The model experimentally mimics CKD by reducing nephron number, resulting in renal insufficiency. Presently, there is a lack of translation of pre-clinical findings into successful clinical results. The pre-clinical nephrology field would benefit from reproducible progressive renal disease models in mice in order to avail of more widely available transgenics and experimental tools to dissect mechanisms of disease. Here we evaluate if a simplified single step subtotal nephrectomy (STNx) model performed in the 129S2/SV mouse can recapitulate the renal and cardiac changes observed in patients with CKD in a reproducible and robust way. The single step STNx surgery was well-tolerated and resulted in clinically relevant outcomes including hypertension, increased urinary albumin:creatinine ratio, and significantly increased serum creatinine, phosphate and urea. STNx mice developed significant left ventricular hypertrophy without reduced ejection fraction or cardiac fibrosis. Analysis of intra-renal inflammation revealed persistent recruitment of Ly6Chi monocytes transitioning to pro-fibrotic inflammatory macrophages in STNx kidneys. Unlike 129S2/SV mice, C57BL/6 mice exhibited renal fibrosis without proteinuria, renal dysfunction, or cardiac pathology. Therefore, the 129S2/SV genetic background is susceptible to induction of progressive proteinuric renal disease and cardiac hypertrophy using our refined, single-step flank STNx method. This reproducible model could be used to study the systemic pathophysiological changes induced by CKD in the kidney and the heart, intra-renal inflammation and for testing new therapies for CKD.
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Affiliation(s)
- James O'Sullivan
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Sarah Louise Finnie
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Oliver Teenan
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Carolynn Cairns
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew Boyd
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Matthew A Bailey
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Adrian Thomson
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Jeremy Hughes
- Centre for Inflammation, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Cécile Bénézech
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Bryan Ronald Conway
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
| | - Laura Denby
- Centre for Cardiovascular Science, Queen's Medical Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
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25
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Salloum FN, Chau VQ. Osteopontin in HFpEF: More Than Just a Remodeling-Specific Biomarker. J Am Coll Cardiol 2019; 73:2719-2721. [PMID: 31146817 DOI: 10.1016/j.jacc.2019.03.477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 03/19/2019] [Indexed: 11/24/2022]
Affiliation(s)
- Fadi N Salloum
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
| | - Vinh Q Chau
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
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26
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Liu S. Heart-kidney interactions: mechanistic insights from animal models. Am J Physiol Renal Physiol 2019; 316:F974-F985. [PMID: 30838876 DOI: 10.1152/ajprenal.00624.2017] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pathological changes in the heart or kidney can instigate the release of a cascade of cardiorenal mediators that promote injury in the other organ. Combined dysfunction of heart and kidney is referred to as cardiorenal syndrome (CRS) and has gained considerable attention. CRS has been classified into five distinct entities, each with different major pathophysiological changes. Despite the magnitude of the public health problem of CRS, the underlying mechanisms are incompletely understood, and effective intervention is unavailable. Animal models have allowed us to discover pathogenic molecular changes to clarify the pathophysiological mechanisms responsible for heart-kidney interactions and to enable more accurate risk stratification and effective intervention. Here, this article focuses on the use of currently available animal models to elucidate mechanistic insights in the clinical cardiorenal phenotype arising from primary cardiac injury, primary renal disease with special emphasis of chronic kidney disease-specific risk factors, and simultaneous cardiorenal/renocardiac dysfunction. The development of novel animal models that recapitulate more closely the cardiorenal phenotype in a clinical scenario and discover the molecular basis of this condition will be of great benefit.
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Affiliation(s)
- Shan Liu
- School of Medicine, South China University of Technology , Guangzhou , China
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27
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Sárközy M, Gáspár R, Zvara Á, Siska A, Kővári B, Szűcs G, Márványkövi F, Kovács MG, Diószegi P, Bodai L, Zsindely N, Pipicz M, Gömöri K, Kiss K, Bencsik P, Cserni G, Puskás LG, Földesi I, Thum T, Bátkai S, Csont T. Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212. Sci Rep 2019; 9:1302. [PMID: 30718600 PMCID: PMC6362219 DOI: 10.1038/s41598-018-37690-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 12/12/2018] [Indexed: 12/22/2022] Open
Abstract
Chronic kidney disease (CKD) is a public health problem that increases the risk of cardiovascular morbidity and mortality. Heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction is a common cardiovascular complication of CKD. MicroRNA-212 (miR-212) has been demonstrated previously to be a crucial regulator of pathologic LVH in pressure-overload-induced heart failure via regulating the forkhead box O3 (FOXO3)/calcineurin/nuclear factor of activated T-cells (NFAT) pathway. Here we aimed to investigate whether miR-212 and its hypertrophy-associated targets including FOXO3, extracellular signal-regulated kinase 2 (ERK2), and AMP-activated protein kinase (AMPK) play a role in the development of HFpEF in CKD. CKD was induced by 5/6 nephrectomy in male Wistar rats. Echocardiography and histology revealed LVH, fibrosis, preserved systolic function, and diastolic dysfunction in the CKD group as compared to sham-operated animals eight and/or nine weeks later. Left ventricular miR-212 was significantly overexpressed in CKD. However, expressions of FOXO3, AMPK, and ERK2 failed to change significantly at the mRNA or protein level. The protein kinase B (AKT)/FOXO3 and AKT/mammalian target of rapamycin (mTOR) pathways are also proposed regulators of LVH induced by pressure-overload. Interestingly, phospho-AKT/total-AKT ratio was increased in CKD without significantly affecting phosphorylation of FOXO3 or mTOR. In summary, cardiac overexpression of miR-212 in CKD failed to affect its previously implicated hypertrophy-associated downstream targets. Thus, the molecular mechanism of the development of LVH in CKD seems to be independent of the FOXO3, ERK1/2, AMPK, and AKT/mTOR-mediated pathways indicating unique features in this form of LVH.
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Affiliation(s)
- Márta Sárközy
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary.
| | - Renáta Gáspár
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Ágnes Zvara
- Laboratory for Functional Genomics, Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, H-6701, Szeged, Hungary
| | - Andrea Siska
- Department of Laboratory Medicine, Faculty of Medicine, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary
| | - Bence Kővári
- Department of Pathology, University of Szeged, Állomás utca 1, Szeged, H-6725, Hungary
| | - Gergő Szűcs
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Fanni Márványkövi
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Mónika G Kovács
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Petra Diószegi
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - László Bodai
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, Szeged, H-6726, Hungary
| | - Nóra Zsindely
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, Szeged, H-6726, Hungary
| | - Márton Pipicz
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Kamilla Gömöri
- Cardiovascular Research Group, Department of Biochemistry, Faculty of Medicine, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Krisztina Kiss
- Cardiovascular Research Group, Department of Biochemistry, Faculty of Medicine, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Péter Bencsik
- Cardiovascular Research Group, Department of Biochemistry, Faculty of Medicine, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
| | - Gábor Cserni
- Department of Pathology, University of Szeged, Állomás utca 1, Szeged, H-6725, Hungary
| | - László G Puskás
- Laboratory for Functional Genomics, Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, H-6701, Szeged, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, Faculty of Medicine, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary
| | - Thomas Thum
- IMTTS, Hannover Medical School, Carl-Neuberg Strasse 1, Hannover, 30625, Germany
| | - Sándor Bátkai
- IMTTS, Hannover Medical School, Carl-Neuberg Strasse 1, Hannover, 30625, Germany
| | - Tamás Csont
- Metabolic Diseases and Cell Signaling Group, Department of Biochemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary
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28
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Kieswich JE, Chen J, Alliouachene S, Caton PW, McCafferty K, Thiemermann C, Yaqoob MM. A novel model of reno-cardiac syndrome in the C57BL/ 6 mouse strain. BMC Nephrol 2018; 19:346. [PMID: 30509210 PMCID: PMC6278034 DOI: 10.1186/s12882-018-1155-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 11/26/2018] [Indexed: 01/06/2023] Open
Abstract
Background The end stage renal disease population has a 20 fold higher incidence of cardiovascular mortality compared to the overall population. The development of reno-cardiac syndrome in these patients will result in cardiovascular events to be the cause of 50% of fatalities. There is therefore a need to research improved therapeutic strategies to combat renal cardiac pathologies. Murine in vivo models contribute greatly to such research allowing for specific genetic modification and reduced miscellany, however there is currently no reliable model of reno-cardiac syndrome in the most common genetically modified mouse strain, the C57BL/6. In this study we have manipulated an established model of chronic renal disease using adenine infused diet and prolonged the course of its pathology achieving chronic renal failure and subsequent reno-cardiac syndrome in the C57BL/6 mouse. Methods Eight week-old male C57BL/ 6 mice were acclimatised for 7 days before administration of a 0.15% adenine diet or control diet for 20 weeks. Cardiac function was assessed in mice at week 20 by echocardiography. At experiment termination blood and urine samples were analysed biochemically and organ dysfunction/injury was determined using immunoblotting and immunohistochemistry. Results Administration of 0.15% adenine diet caused progressive renal failure resulting in reno-cardiac syndrome. At endpoint uraemia was confirmed by blood biochemistry which in the adenine fed mice showed significant increases in serum creatinine, urea, calcium (P < 0.0001) potassium (P < 0.05), and a significantly reduced glomerular filtration rate (P < 0.05). Reno-cardiac syndrome was confirmed by a significantly increased heart to body weight ratio (P < 0.0001) and echocardiography which showed significant reductions in percentage of ejection fraction, fractional shortening, fractional area change, (P < 0.0001) and an increase in left ventricular end diastolic volume (P < 0.05). Immunoblotting of kidney and heart tissue showed increased apoptosis (caspase 3) and fibrosis (fibronectin) and increases in the cardiac levels of phosphorylated Akt, and renal total Akt. Immunohistochemistry for α-SMA, collagen 1 and collagen 3 further confirmed fibrosis. Conclusions We present a novel regimen of adenine diet which induces both chronic kidney disease and reno-cardiac syndrome in the C57/BL6 mouse strain. The non-surgical nature of this model makes it highly reproducible compared to other models currently available. Electronic supplementary material The online version of this article (10.1186/s12882-018-1155-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Julius E Kieswich
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London, E1 1BB, UK. .,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
| | - Jianmin Chen
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London, E1 1BB, UK
| | - Samira Alliouachene
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London, E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Paul W Caton
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, Hodgkin Building, Guy's Campus, London, UK
| | - Kieran McCafferty
- Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Christoph Thiemermann
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London, E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Muhammad M Yaqoob
- Diabetic Kidney Disease Centre, Renal Unit, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London, E1 1BB, UK.,Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
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29
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Ham O, Jin W, Lei L, Huang HH, Tsuji K, Huang M, Roh J, Rosenzweig A, Lu HAJ. Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril. Sci Rep 2018; 8:16087. [PMID: 30382174 PMCID: PMC6208335 DOI: 10.1038/s41598-018-34216-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 10/04/2018] [Indexed: 12/27/2022] Open
Abstract
Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.
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Affiliation(s)
- Onju Ham
- Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - William Jin
- College of Arts & Sciences, Washington University in St. Louis, St. Louis, MO, 63130, USA
| | - Lei Lei
- Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Hui Hui Huang
- Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Kenji Tsuji
- Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Ming Huang
- Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jason Roh
- Corrigan Minehan Heart Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Anthony Rosenzweig
- Corrigan Minehan Heart Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Hua A Jenny Lu
- Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
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30
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Wei X, Wu W, Li L, Lin J, Liu Q, Gan L, Ou S. Bone Morphogenetic Proteins 2/4 Are Upregulated during the Early Development of Vascular Calcification in Chronic Kidney Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8371604. [PMID: 29850574 PMCID: PMC5925148 DOI: 10.1155/2018/8371604] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 02/12/2018] [Accepted: 03/04/2018] [Indexed: 02/06/2023]
Abstract
Vascular calcification is a main cause of increased cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study aimed to investigate the role of the bone morphogenetic protein (BMP) signaling pathway in the early development of vascular calcification in CKD. A CKD vascular calcification rat model was established by providing rats with a 1.8% high-phosphorus diet and an intragastric administration of 2.5% adenine suspension. The kidney and aortic pathologies were analyzed. Blood biochemical indicators, serum BMP-2 and BMP-4 levels, and aortic calcium content were determined. The expression levels of BMP-2, BMP-4, bone morphogenetic protein receptor-IA (BMPR-IA), and matrix Gla protein (MGP) in aorta were examined by quantitative real-time polymerase chain reaction and immunohistochemistry. Compared with the normal control (Nor) rats, the CKD rats exhibited a significantly decreased body weight and an increased kidney weight as well as abnormal renal function and calcium-phosphorus metabolism. Aortic von Kossa and Alizarin red staining showed massive granular deposition and formation of calcified nodules in aorta at 8 weeks. The aortic calcium content was significantly increased, which was positively correlated with the serum BMP-2 (r = 0.929; P < 0.01) and serum BMP-4 (r = 0.702; P < 0.01) levels in CKD rats. The rat aortic BMP-2 mRNA level in the CKD rats was persistently increased, and the BMP-4 mRNA level was prominently increased at the 4th week, declining thereafter. Strong staining of BMP-2, BMP-4, BMPR-IA, and MGP proteins was observed in the tunica media of the aorta from the 4th week after model induction. In conclusion, activation of the BMP signaling pathway is involved in the early development of vascular calcification in CKD. Therefore, elevated serum BMP-2 and BMP-4 levels may serve as serum markers for CKD vascular calcification.
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Affiliation(s)
- Xiao Wei
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Weihua Wu
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Li Li
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Jiaru Lin
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Qi Liu
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Linwang Gan
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Santao Ou
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
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31
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Giam B, Kuruppu S, Chu PY, Smith AI, Marques FZ, Fiedler A, Horlock D, Kiriazis H, Du XJ, Kaye DM, Rajapakse NW. N-Acetylcysteine Attenuates the Development of Renal Fibrosis in Transgenic Mice with Dilated Cardiomyopathy. Sci Rep 2017; 7:17718. [PMID: 29255249 PMCID: PMC5735149 DOI: 10.1038/s41598-017-17927-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 12/01/2017] [Indexed: 02/02/2023] Open
Abstract
Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC;40 mg/kg/day; 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function (P ≥ 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice (P ≤ 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice (P < 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice (P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter (P < 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM.
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Affiliation(s)
- Beverly Giam
- Baker Heart and Diabetes Institute, Melbourne, Australia. .,Central Clinical School, Monash University, Melbourne, Australia.
| | - Sanjaya Kuruppu
- Biomedicine Discovery Institute, Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Australia
| | - Po-Yin Chu
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - A Ian Smith
- Biomedicine Discovery Institute, Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Australia
| | - Francine Z Marques
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Central Clinical School, Monash University, Melbourne, Australia
| | - April Fiedler
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Duncan Horlock
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Xiao-Jun Du
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - David M Kaye
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Department of Medicine, Monash University, Melbourne, Australia
| | - Niwanthi W Rajapakse
- Baker Heart and Diabetes Institute, Melbourne, Australia.,School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia
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32
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Valero-Muñoz M, Backman W, Sam F. Murine Models of Heart Failure with Preserved Ejection Fraction: a "Fishing Expedition". JACC Basic Transl Sci 2017; 2:770-789. [PMID: 29333506 PMCID: PMC5764178 DOI: 10.1016/j.jacbts.2017.07.013] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/25/2017] [Accepted: 07/27/2017] [Indexed: 12/28/2022]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of HF in the presence of a normal left ventricular (LV) ejection fraction (EF). Despite accounting for up to 50% of all clinical presentations of HF, the mechanisms implicated in HFpEF are poorly understood, thus precluding effective therapy. The pathophysiological heterogeneity in the HFpEF phenotype also contributes to this disease and likely to the absence of evidence-based therapies. Limited access to human samples and imperfect animal models that completely recapitulate the human HFpEF phenotype have impeded our understanding of the mechanistic underpinnings that exist in this disease. Aging and comorbidities such as atrial fibrillation, hypertension, diabetes and obesity, pulmonary hypertension and renal dysfunction are highly associated with HFpEF. Yet, the relationship and contribution between them remains ill-defined. This review discusses some of the distinctive clinical features of HFpEF in association with these comorbidities and highlights the advantages and disadvantage of commonly used murine models, used to study the HFpEF phenotype.
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Affiliation(s)
- Maria Valero-Muñoz
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Warren Backman
- Evans Department of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Flora Sam
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
- Evans Department of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts
- Cardiovascular Section, Boston University School of Medicine, Boston, Massachusetts
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Yang JY, Huang JW, Chen L, Chen YY, Pai MF, Tung KT, Peng YS, Hung KY. Frequency of Early Predialysis Nephrology Care and Postdialysis Cardiovascular Events. Am J Kidney Dis 2017; 70:164-172. [DOI: 10.1053/j.ajkd.2016.12.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 12/19/2016] [Indexed: 11/11/2022]
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Smith ER, Hewitson TD, Cai MMX, Aghagolzadeh P, Bachtler M, Pasch A, Holt SG. A novel fluorescent probe-based flow cytometric assay for mineral-containing nanoparticles in serum. Sci Rep 2017; 7:5686. [PMID: 28720774 PMCID: PMC5515983 DOI: 10.1038/s41598-017-05474-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 05/30/2017] [Indexed: 12/20/2022] Open
Abstract
Calciprotein particles, nanoscale aggregates of insoluble mineral and binding proteins, have emerged as potential mediators of phosphate toxicity in patients with Chronic Kidney Disease. Although existing immunochemical methods for their detection have provided compelling data, these approaches are indirect, lack specificity and are subject to a number of other technical and theoretical shortcomings. Here we have developed a rapid homogeneous fluorescent probe-based flow cytometric method for the detection and quantitation of individual mineral-containing nanoparticles in human and animal serum. This method allows the discrimination of membrane-bound from membrane-free particles and different mineral phases (amorphous vs. crystalline). Critically, the method has been optimised for use on a conventional instrument, without the need for manual hardware adjustments. Using this method, we demonstrate a consistency in findings across studies of Chronic Kidney Disease patients and commonly used uraemic animal models. These studies demonstrate that renal dysfunction is associated with the ripening of calciprotein particles to the crystalline state and reveal bone metabolism and dietary mineral as important modulators of circulating levels. Flow cytometric analysis of calciprotein particles may enhance our understanding of mineral handling in kidney disease and provide a novel indicator of therapeutic efficacy for interventions targeting Chronic Kidney Disease-Mineral Bone Disorder.
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Affiliation(s)
- Edward R Smith
- Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia. .,Department of Medicine - Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
| | - Tim D Hewitson
- Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.,Department of Medicine - Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Michael M X Cai
- Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.,Department of Medicine - Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Matthias Bachtler
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Andreas Pasch
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Stephen G Holt
- Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.,Department of Medicine - Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
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Samuel CS, Royce SG, Hewitson TD, Denton KM, Cooney TE, Bennett RG. Anti-fibrotic actions of relaxin. Br J Pharmacol 2017; 174:962-976. [PMID: 27250825 PMCID: PMC5406285 DOI: 10.1111/bph.13529] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/19/2016] [Accepted: 05/23/2016] [Indexed: 12/19/2022] Open
Abstract
Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosis-related disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, anti-hypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic. LINKED ARTICLES This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.
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Affiliation(s)
- C S Samuel
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of PharmacologyMonash UniversityMelbourneVic.Australia
| | - S G Royce
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of PharmacologyMonash UniversityMelbourneVic.Australia
| | - T D Hewitson
- Department of NephrologyRoyal Melbourne HospitalMelbourneVic.Australia
| | - K M Denton
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of PhysiologyMonash UniversityMelbourneVic.Australia
| | - T E Cooney
- University of Pittsburgh Medical Centre (UPMC) HamotEriePAUSA
| | - R G Bennett
- Research Service 151VA Nebraska‐Western Iowa Health Care SystemOmahaNEUSA
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNEUSA
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von Scheidt M, Zhao Y, Kurt Z, Pan C, Zeng L, Yang X, Schunkert H, Lusis AJ. Applications and Limitations of Mouse Models for Understanding Human Atherosclerosis. Cell Metab 2017; 25:248-261. [PMID: 27916529 PMCID: PMC5484632 DOI: 10.1016/j.cmet.2016.11.001] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 08/26/2016] [Accepted: 11/03/2016] [Indexed: 12/13/2022]
Abstract
Most of the biological understanding of mechanisms underlying coronary artery disease (CAD) derives from studies of mouse models. The identification of multiple CAD loci and strong candidate genes in large human genome-wide association studies (GWASs) presented an opportunity to examine the relevance of mouse models for the human disease. We comprehensively reviewed the mouse literature, including 827 literature-derived genes, and compared it to human data. First, we observed striking concordance of risk factors for atherosclerosis in mice and humans. Second, there was highly significant overlap of mouse genes with human genes identified by GWASs. In particular, of the 46 genes with strong association signals in CAD GWASs that were studied in mouse models, all but one exhibited consistent effects on atherosclerosis-related phenotypes. Third, we compared 178 CAD-associated pathways derived from human GWASs with 263 from mouse studies and observed that the majority were consistent between the species.
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Affiliation(s)
- Moritz von Scheidt
- Deutsches Herzzentrum München, Technische Universität München, 80333 Munich, Germany
| | - Yuqi Zhao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zeyneb Kurt
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Calvin Pan
- Departments of Medicine, Microbiology, and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Lingyao Zeng
- Deutsches Herzzentrum München, Technische Universität München, 80333 Munich, Germany
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Heribert Schunkert
- Deutsches Herzzentrum München, Technische Universität München, 80333 Munich, Germany; Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Aldons J Lusis
- Departments of Medicine, Microbiology, and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Baba A, Tachi M, Ejima Y, Endo Y, Toyama H, Saito K, Abe N, Yamauchi M, Miura C, Kazama I. Less contribution of mast cells to the progression of renal fibrosis in Rat kidneys with chronic renal failure. Nephrology (Carlton) 2017; 22:159-167. [DOI: 10.1111/nep.12733] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/15/2015] [Accepted: 01/18/2016] [Indexed: 11/30/2022]
Affiliation(s)
- Asuka Baba
- Department of Physiology I; Tohoku University Graduate School of Medicine; Seiryo-cho, Aoba-ku Sendai Miyagi Japan
- Department of Plastic and Reconstructive Surgery; Tohoku University Graduate School of Medicine
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery; Tohoku University Graduate School of Medicine
| | - Yutaka Ejima
- Department of Anesthesiology; Tohoku University Hospital
| | - Yasuhiro Endo
- Department of Anesthesiology; Tohoku University Hospital
| | - Hiroaki Toyama
- Department of Anesthesiology; Tohoku University Hospital
| | - Kazutomo Saito
- Department of Anesthesiology; Tohoku University Hospital
| | - Nozomu Abe
- Department of Anesthesiology; Tohoku University Hospital
| | | | - Chieko Miura
- Department of Plastic and Reconstructive Surgery; Tohoku University Graduate School of Medicine
| | - Itsuro Kazama
- Department of Physiology I; Tohoku University Graduate School of Medicine; Seiryo-cho, Aoba-ku Sendai Miyagi Japan
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Pinheiro da Silva AL, Vaz da Silva MJ. Type 4 cardiorenal syndrome. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2016. [DOI: 10.1016/j.repce.2016.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Pinheiro da Silva AL, Vaz da Silva MJ. Type 4 cardiorenal syndrome. Rev Port Cardiol 2016; 35:601-616. [PMID: 27712930 DOI: 10.1016/j.repc.2016.06.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Accepted: 06/04/2016] [Indexed: 12/25/2022] Open
Abstract
The Acute Dialysis Quality Initiative consensus conference proposed a classification of cardiorenal syndrome (CRS), aiming for a better delineation of each subtype. Although the exact pathophysiology of type 4 CRS is not completely understood, the mechanisms involved are probably multifactorial. There is growing evidence that oxidative stress is a major connector in the development and progression of type 4 CRS. Giving its complexity, poor prognosis and increasing incidence, type 4 CRS is becoming a significant public health problem. Patients with chronic kidney disease are particularly predisposed to cardiac dysfunction, due to the high prevalence of traditional cardiovascular risk factors in this population, but the contribution of risk factors specific to chronic kidney disease should also be taken into account. Much remains to be elucidated about type 4 CRS: despite progress over the last decade, there are still significant questions regarding its pathophysiology and there is as yet no specific therapy. A better understanding of the mechanisms involved may provide potential targets for intervention. The present review will provide a brief description of the definition, epidemiology, diagnosis, prognosis, biomarkers and management strategies of type 4 CRS, and the pathophysiological mechanisms and risk factors presumably involved in its development will be particularly highlighted.
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DeFreitas MJ, Katsoufis CP, Abitbol CL. Cardio-renal consequences of low birth weight and preterm birth. PROGRESS IN PEDIATRIC CARDIOLOGY 2016. [DOI: 10.1016/j.ppedcard.2016.01.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Therapeutic evaluation of rutin in two-kidney one-clip model of renovascular hypertension in rat. Life Sci 2016; 150:89-94. [PMID: 26920631 DOI: 10.1016/j.lfs.2016.02.080] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 02/19/2016] [Accepted: 02/22/2016] [Indexed: 12/31/2022]
Abstract
AIM The current investigation, designed to investigate the role of rutin in two-kidney one-clip (2K1C) induced renovascular dysfunction associated with hypertension in rat. MAIN METHODS The renovascular hypertension was developed by the application of vascular clip on left renal artery in rats; the right kidney was kept as such throughout the experimental protocol. The rutin (200 and 300 mg/kg; p.o.) and aliskiren (50mg/kg; p.o.) were administered for 9 consecutive days. The battery of pathophysiological tests i.e., systolic pressure, diastolic pressure and heart rate were performed to assess the anti-hypertensive effect of rutin. In addition, changes of kidney weight/body weight (KW/BW) ratio along with plasma renin content and renal tissue biomarkers i.e., thiobarbituric acid reactive substance (TBAR) and reduced glutathione (GSH) levels were estimated. KEY FINDINGS The administration of rutin significantly (P<0.05) attenuated the 2K1C of left kidney induced elevated systolic and diastolic pressure in a dose dependent manner. In addition, it also reduces the ratio of KW/BW along with a decrease in plasma renin content, tissue TBARS and increase the GSH levels. There were no significant changes observed in heart rate. Similar results were observed in aliskiren treated group. SIGNIFICANCE The anti-hypertensive effect of rutin may be a useful herbal medicine for the management of hypertension due to its potential free radical scavenging, inhibition of lipid peroxidation and plasma renin inhibitory action.
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