title: Suppression of NLRP3 Inflammasome Activation Ameliorates Chronic Kidney Disease-Induced Cardiac Fibrosis and Diastolic Dysfunction.
abstract: Cardiac fibrosis is a common finding in patients with chronic kidney disease. Here, we investigate the cardio-renal effects of theracurmin, a novel formulation of the polyphenolic compound curcumin, in a rat model of chronic kidney disease. Briefly, Sprague-Dawley rats were randomized to undergo sham or subtotal nephrectomy (SNx) surgery. At 3 weeks post surgery, SNx animals were further randomized to received theracurmin via once daily oral gavage or vehicle for 5 consecutive weeks. At 8 weeks post surgery, cardiac function was assessed via echocardiography and pressure volume loop analysis, followed by LV and renal tissue collection for analysis. SNx animals developed key hallmarks of renal injury including hypertension, proteinuria, elevated blood urea nitrogen, and glomerulosclerosis. Renal injury in SNx animals was also associated with significant diastolic dysfunction, macrophage infiltration, and cardiac NLRP3 inflammasome activation. Treatment of SNx animals with theracurmin improved structural and functional manifestations of cardiac injury associated with renal failure and also attenuated cardiac NLRP3 inflammasome activation and mature IL-1β release. Taken together, our findings suggest a significant role for the NLRP3 inflammasome in renal injury-induced cardiac dysfunction and presents inflammasome attenuation as a unique strategy to prevent adverse cardiac remodeling in the setting of chronic kidney disease.
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Bugyei-Twum
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.
authors.forename: Armin
authors.initials: A
authors.lastname: Abadeh
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.
authors.forename: Golam
authors.initials: G
authors.lastname: Kabir
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's hospital, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Division of Cardiology, St. Michael's hospital, Toronto, Ontario, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D003971:Diastole; D004452:Echocardiography; D005355:Fibrosis / Q000473:pathology*; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007676:Kidney Failure, Chronic; D008264:Macrophages / Q000166:cytology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009392:Nephrectomy; D059808:Polyphenols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D059808:Polyphenols