Cardiorenal disease connection during post-menopause: The protective role of estrogen in uremic toxins induced microvascular dysfunction.
Female gender, post-menopause, chronic kidney disease (CKD) and (CKD linked) microvascular disease are important risk factors for developing heart failure with preserved ejection fraction (HFpEF). Enhancing our understanding of the interrelation between these risk factors could greatly benefit the identification of new drug targets for future therapy. This review discusses the evidence for the protective role of estradiol (E2) in CKD-associated microvascular disease and related HFpEF. Elevated circulating levels of uremic toxins (UTs) during CKD may act in synergy with hormonal changes during post-menopause and could lead to coronary microvascular endothelial dysfunction in HFpEF. To elucidate the molecular mechanism involved, published transcriptome datasets of indoxyl sulfate (IS), high inorganic phosphate (HP) or E2treated human derived endothelial cells from the NCBI Gene Expression Omnibus database were analyzed. In total, 36 genes overlapped in both IS- and HP-activated gene sets, 188 genes were increased by UTs (HP and/or IS) and decreased by E2, and 572 genes were decreased by UTs and increased by E2. Based on a comprehensive in silico analysis and literature studies of collected gene sets, we conclude that CKD-accumulated UTs could negatively impact renal and cardiac endothelial homeostasis by triggering extensive inflammatory responses and initiating dysregulation of angiogenesis. E2may protect (myo)endothelium by inhibiting UTs-induced inflammation and ameliorating UTs-related uremic bleeding and thrombotic diathesis via restored coagulation capacity and hemostasis in injured vessels.
Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, The Netherlands.
Jiayi
J
Pei
Department of Cardiology, University Medical Center Utrecht, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands.
Magdalena
M
Harakalova
Experimental Cardiology Laboratory, Department of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.
Hester
H
den Ruijter
Experimental Cardiology Laboratory, Department of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.
Gerard
G
Pasterkamp
Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands.
Dirk J
DJ
Duncker
Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, The Netherlands.
Marianne C
MC
Verhaar
Department of Cardiology, University Medical Center Utrecht, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands; Institute of Cardiovascular Science, University College London, United Kingdom.
Folkert W
FW
Asselbergs
Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, The Netherlands; Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: K.L.Cheng-2@umcutrecht.nl.
Caroline
C
Cheng
D059347:Cardio-Renal Syndrome / Q000097:blood* / Q000453:epidemiology / Q000517:prevention & control; D004967:Estrogens / Q000097:blood* / Q000627:therapeutic use; D005260:Female; D053263:Gene Regulatory Networks / Q000502:physiology; D006801:Humans; D055806:Microvessels / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017698:Postmenopause / Q000097:blood* / Q000187:drug effects; D014511:Uremia / Q000097:blood* / Q000453:epidemiology / Q000517:prevention & control; D014652:Vascular Diseases / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control
D004967:Estrogens
Cardiorenal syndrome; Estrogen; High phosphate; Indoxyl sulfate; Menopause; Microvascular dysfunction