Physiology - Research Publications

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Author: Harrap, Stephen × Author: Charchar, Fadi × Author: Burrell, Louise ×

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    Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney
    Jiang, X ; Eales, JM ; Scannali, D ; Nazgiewicz, A ; Prestes, P ; Maier, M ; Denniff, M ; Xu, X ; Saluja, S ; Cano-Gamez, E ; Wystrychowski, W ; Szulinska, M ; Antczak, A ; Byars, S ; Skrypnik, D ; Glyda, M ; Krol, R ; Zywiec, J ; Zukowska-Szczechowska, E ; Burrell, LM ; Woolf, AS ; Greenstein, A ; Bogdanski, P ; Keavney, B ; Morris, AP ; Heagerty, A ; Williams, B ; Harrap, SB ; Trynka, G ; Samani, NJ ; Guzik, TJ ; Charchar, FJ ; Tomaszewski, M (OXFORD UNIV PRESS, 2020-12-21)
    AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
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    Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure
    Marques, FZ ; Prestes, PR ; Byars, SG ; Ritchie, SC ; Wurtz, P ; Patel, SK ; Booth, SA ; Rana, I ; Minoda, Y ; Berzins, SP ; Curl, CL ; Bell, JR ; Wai, B ; Srivastava, PM ; Kangas, AJ ; Soininen, P ; Ruohonen, S ; Kahonen, M ; Lehtimaki, T ; Raitoharju, E ; Havulinna, A ; Perola, M ; Raitakari, O ; Salomaa, V ; Ala-Korpela, M ; Kettunen, J ; McGlynn, M ; Kelly, J ; Wlodek, ME ; Lewandowski, PA ; Delbridge, LM ; Burrell, LM ; Inouye, M ; Harrap, SB ; Charchar, FJ (WILEY, 2017-06-01)
    BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.