Abstract 13764: Renalase Peptide Agonist Therapy Normalizes the Cardiac Response to Pressure Overload in Chronic Kidney Disease
Circulation(2022)
摘要
Introduction: Chronic kidney disease (CKD) increases susceptibility to heart disease. The mechanisms remain unclear and may include dysregulation of autocrine, paracrine or circulating factors. Renalase (RNLS) is a secreted protein expressed in the kidney and heart with potent pro-survival and anti-inflammatory properties. Cardiac pressure overload by transverse aortic constriction (TAC) is associated with increased cardiac RNLS expression in normal mice, while mice with CKD have decreased cardiac RNLS. We hypothesized that CKD would alter the hypertrophic response to TAC, and that therapy with exogenous mouse-specific RNLS agonist peptide (mRNLS-ap) would normalize the response. Methods: In wild-type male C57BL/6J mice, CKD was induced by two doses of cisplatin (15mg/kg SQ), two weeks apart (validated and published CKD model). Non-CKD mice received 0.9% saline. TAC was induced 8 weeks after first cisplatin dose. Control mice (sham) had aortic arch exposure without constriction. mRNLS-ap (20 mg/kg SQ) was injected twice daily for 14 days, starting one day before surgery. Serial echocardiograms were performed. Results: CKD groups had similar degrees of renal failure. Mean aortic gradients were comparable after TAC. Kidney RNLS protein expression was 44% less in CKD (n=8) than non-CKD (n=4) mice at sacrifice (12 weeks after surgery) (p<0.001). One-week post-surgery, untreated CKD-TAC mice showed impaired hypertrophy with smaller increase (over baseline pre-TAC values) in LV wall thickness than non-CKD-TAC mice (15 ± 5% vs. 35 ± 4%, n=12 each; p<0.001). Four weeks post-surgery, the response normalized with similar LV wall thickness increases in CKD-TAC and non-CKD-TAC mice (31 ± 8% vs. 29 ± 3%, n=11-12 each; p>0.99). Sham groups did not change. One-week post-surgery with exogenous mRNLS-ap therapy, the difference in LV wall thickness increase between the CKD-TAC and non-CKD-TAC hearts was eliminated (28 ± 6%, n=9 vs. 24 ± 8%, n=4; p>0.95). Sham groups did not change. Conclusions: RNLS expression is reduced in cisplatin-induced CKD, and associated with a delayed LV hypertrophic response to TAC. RNLS agonist therapy corrects this delay. Plasma and/or cardiac RNLS are important early mediators of cardiac adaptation to pressure overload stress in CKD.
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关键词
renalase peptide agonist therapy,chronic kidney disease,kidney disease,cardiac response
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