Fibrosis is a key component of pathologic remodeling in multiple tissues, no therapies specifically target maladaptive fibrosis. Heart failure (HF), the final manifestation of many cardiovascular pathologies, is a devastating disease with poor prognosis, exacerbated by concomitant kidney dysfunction. Cardiorenal syndrome (CRS) is the pathologic crosstalk between the heart and kidney, including increased fibrosis and failure of both organsd. Worsening renal function co-exists with HF in CRS2 and is a strong predictor of mortality in HF patients. Pathologically activated fibroblasts transition to myofibroblasts (MFs) to exacerbate tissue remodeling. Novel POSTNMerCreMer and Tcf21MerCreMer knock-in mice permit targeted, inducible fibroblast modulation in vivo. In HF or kidney injury, chronic stimulation of G-protein coupled receptors (GPCRs) elicits pathologic upregulation of GPCR kinase 2 (GRK2) that is recruited to membrane G?? subunits to modulate agonist-occupied GPCRs. Systemic delivery of our novel small molecule G??-GRK2 inhibitor, gallein, attenuates fibrosis, HF and GRK2 expression following transverse aortic constriction (TAC). GRK2 ablation in activated fibroblasts (GRK2fl/fl-POSTNMerCreMer) after cardiac ischemia/reperfusion (I/R) injury was cardioprotective, with no further protection conferred by gallein. TAC or I/R injury resulted in CRS2, including kidney fibrosis and dysfunction, as well as elevation of GRK2 and endothelin (ET) characteristic of renal dysfunction. Gallein attenuated kidney fibrosis, dysfunction, GRK2 expression and ET following TAC or I/R. G??-GRK2 inhibition also attenuated renal dysfunction and fibrosis following acute renal I/R injury, suggesting a direct protective effect of blocking G??-GRK2 signaling in kidney dysfunction. Novel Cre mice ablate GRK2 in either kidney pericytes (FoxD1Cre) or epithelial cells (Six2Cre) and will be used to evaluate the role of G??- GRK2 signaling in kidney fibrosis. Our hypothesis is that G??-GRK2 plays an important role in pathologic fibrotic remodeling in both HF progression and kidney dysfunction and that its inhibition holds therapeutic promise for fibrotic remodeling in HF, kidney injury and CRS2. To address our hypothesis, we propose the following:
Aim 1. Determine the therapeutic efficacy and specificity of G??-GRK2 inhibition or ablation in cardiac fibrosis and CRS2.
Aim 2. Determine the therapeutic efficacy and specificity of G??-GRK2 inhibition or ablation in renal fibrosis and CRS2.
Specific Aim 3 : Elucidate the cellular mechanisms of G??-GRK2 inhibition in cardiac and renal fibroblasts and validate G??-GRK2 as a therapeutic target in mouse and human cardiac fibrosis, kidney fibrosis and HF. We believe this proposal, with G??-GRK2 inhibitory compounds validated in various GRK2 null mice in cardiac and renal fibrosis, holds therapeutic promise for HF, CRS2, kidney injury and possibly other fibrotic diseases.
? PROJECT RELEVANCE TO PUBLIC HEALTH Heart failure, the final manifestation of most cardiovascular disease, is a devastating disease with poor prognosis that remains a leading cause of mortality in the United States. Fibrotic remodeling is a key component of disease progression both the heart and the kidney. Heart failure with concomitant kidney failure is known as cardiorenal syndrome (CRS) but remains poorly understood. Renal failure is a significant predictor of poor outcome in heart failure patients. This proposal aims to better understand the molecular and cellular bases of fibrosis in the heart and the kidney, which may lead to the identification of novel therapeutic targets and strategies for treating heart and kidney fibrosis and failure, including CRS.
| Valiente-Alandi, Iñigo; Potter, Sarah J; Salvador, Ane M et al. (2018) Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure. Circulation 138:1236-1252 |
| Travers, Joshua G; Kamal, Fadia A; Valiente-Alandi, Iñigo et al. (2017) Pharmacological and Activated Fibroblast Targeting of G??-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression. J Am Coll Cardiol 70:958-971 |
| Schafer, Allison E; Blaxall, Burns C (2017) G Protein Coupled Receptor-mediated Transactivation of Extracellular Proteases. J Cardiovasc Pharmacol 70:10-15 |
| Kamal, Fadia A; Travers, Joshua G; Schafer, Allison E et al. (2017) G Protein-Coupled Receptor-G-Protein ??-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure. J Am Soc Nephrol 28:197-208 |
| Rudomanova, Valeria; Blaxall, Burns C (2017) Targeting GPCR-G??-GRK2 signaling as a novel strategy for treating cardiorenal pathologies. Biochim Biophys Acta Mol Basis Dis 1863:1883-1892 |
| Travers, Joshua G; Kamal, Fadia A; Robbins, Jeffrey et al. (2016) Cardiac Fibrosis: The Fibroblast Awakens. Circ Res 118:1021-40 |
