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#VECTOR TD VPK DRIVER#
Notably, indoxyl sulfate (IS) has gained popularity in the literature as a driver for cardiovascular disease risk ( 21). Interestingly, some uremic metabolites have been shown to reduce nitric oxide availability within the endothelium of cultured endothelial cells ( 4, 19, 20). There is growing evidence supporting a hypothesis by which uremic metabolites, or toxins, may be key factors linking kidney function to the systemic disease manifestation (hypertension, obesity, muscle wasting, and cardiovascular disease) often present in the patient with CKD.
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Patients with CKD have impaired filtration of endogenous and exogenous waste products (normally filtered by healthy kidneys) that accumulate within the blood, a condition defined as uremia ( 18). Despite these observations, mechanistic data aiming to understand the molecular mechanisms linking CKD to impaired angiogenesis are scarce. Previous studies have demonstrated that rodents with CKD exhibit impaired perfusion recovery and angiogenesis following surgically induced ischemia ( 12, 17). Endothelial cells play key regulatory roles in sprouting angiogenesis that involve both proliferative and migratory actions, which are governed by established angiogenic and metabolic signaling pathways ( 16). This physiological process is especially crucial for ischemic diseases where recovery of tissue perfusion is necessary for survival. Although it is clear that CKD negatively impacts vascular tissues, the underlying molecular mechanisms are incompletely understood and present a significant gap in knowledge that compromises development of effective treatments to improve health outcomes in CKD.Īngiogenesis is a process that involves growth of new blood vessels through either sprouting of new vessels or splitting of existing vessels. Moreover, studies have reported that CKD accelerates development of atherosclerosis ( 12, 13) and impairs angiogenesis ( 14, 15) in rodent models. CKD also increases the likelihood that patients with PAD will present with ischemic ulceration or gangrene, which substantially increases the risk of limb amputation ( 6, 10, 11). For example, patients with peripheral arterial disease (PAD) along with CKD have two to four times higher risk for mortality than patients with PAD but without CKD ( 5– 9). Patients with CKD are at a substantially higher risk for developing cardiovascular disease, which leads to high rates of cardiovascular disease mortality in this population ( 2– 4).
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Taken together, these data define the impact of AHR activation on angiogenesis and highlight the potential for therapeutic AHR antagonists, which may improve angiogenesis in the context of CKD and cardiovascular disease.Ĭhronic kidney disease (CKD) is defined as any condition that causes chronic damage to the kidney that results in a reduction in glomerular filtration rate (GFR) below 60 mL/min/1.73 m 2 for 3 mo or longer and affects an estimated 8%–16% of the global population ( 1). Expression of the CAAHR recapitulated the impaired tube formation and proliferation in cultured endothelial cells and decreased sprouting in aortic ring cultures. Finally, a constitutively active AHR (CAAHR) vector was generated and used to confirm AHR-specific effects.
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Similarly, pharmacological AHR antagonism using resveratrol and CH223191 were also found to rescue angiogenesis in cell and aortic ring cultures. Next, genetic knockdown of the AHR using shRNA was found to rescue endothelial cell tube formation, proliferation, and aortic ring sprouting. Moreover, aortic ring cultures treated with indoxyl sulfate also exhibited decreased sprouting and high AHR activation. In this study, activation of the aryl hydrocarbon receptor (AHR) via indoxyl sulfate, a known uremic metabolite, was found to impair endothelial cell tube formation and proliferation but not migratory function. However, the molecular mechanisms by which uremic metabolites negatively impact endothelial cell biology are not fully understood. There is growing evidence that uremic metabolites, which accumulate in the blood with CKD, have detrimental impacts on endothelial cell health and function. Chronic kidney disease (CKD) is associated with a substantial increased risk of cardiovascular disease.