Date of Award
Medical Doctor (MD)
Gary V. Desir
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, whereas mice with CKD have decreased plasma and cardiac renalase. Our first hypothesis was that CKD alters cardiac structure and function, and the response to pressure overload. Secondly, we hypothesized that therapy with exogenous mouse-specific RNLS agonist peptide (mRNLS-ap) modifies the cardiac response to pressure overload in normal and chronic kidney disease states. 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. Mice were sacrificed for tissue collection at 11 weeks after first cisplatin dose. RESULTS: CKD groups had similar degrees of renal failure, marked by elevated kidney injury molecule-1 and creatinine levels compared to control groups. Mean and peak aortic gradients were comparable after TAC. CKD mice had enhanced systolic contractile function, relative LV hypertrophy and left atrial enlargement without changes in cardiac fibrosis. Significant elevation in IL-6 and TNF-α was also noted in CKD. With pressure overload, CKD mice experienced an earlier loss of contractile function (decline in LV ejection fraction) compared to normal mice. Early treatment during pressure overload with high dose renalase agonist peptide accelerated cardiac hypertrophy and fibrosis, particularly in normal mice. B-type natriuretic peptide gene expression in the left ventricle was increased with pressure overload in both normal and CKD mice, and decreased with mRNLS-ap treatment in CKD. Renalase gene expression in the LV was increased in normal mice but not CKD mice after TAC. With mRNLS-ap, renalase gene expression decreased in normal mice but not CKD mice after TAC. Notably, mRNLS-ap induced elevations in pro-inflammatory cytokines compared to vehicle treatment in both normal and CKD mice. Transient loss of bodyweight and increase in heart rate was also noted in the first week of treatment in normal mice. CONCLUSIONS: Our findings reveal that CKD results in a hyperdynamic and hypertrophic left ventricle, and induces a persistent state of systemic inflammation. CKD (a state of decreased renalase) impairs the ability of the heart to adapt to pressure overload, and renalase agonist treatment accelerates the cardiac hypertrophic and fibrotic response. Our findings support a role for renalase in regulating the cardiac adaptation to stress. A priority for future studies should be to examine the complex interactions between renalase and inflammation, and to investigate dose-related variations in immune and tissue effects of renalase agonist. The study of renalase and its broad actions across many tissues will continue to help uncover fundamental pathways in complex human diseases such as CKD, and generate opportunities for translational development of treatments.
Krishna Kumar Nair, Govind, "Renalase Agonist Therapy And The Cardiac Response To Pressure Overload In Chronic Kidney Disease" (2023). Yale Medicine Thesis Digital Library. 4185.