UCLA

Cardiovascular disease (CVD) is the most common cause of the death among patients with chronic kidney disease (CKD). Fibroblast growth factor (FGF) 23, a potent regulator of the vitamin D system, is markedly upregulated early in CKD, with levels increasing as kidney function declines. Clinical studies suggest connections between FGF23 and cardiovascular complications associated with CKD, as both are strongly correlated to decreased renal output. Vitamin D deficiency is another serious co-morbidity associated with CKD. A key regulator of innate immune function, vitamin D plays an important role in CVD propagated by chronic inflammation. However, the contributions FGF23 and vitamin D to CKD-related cardiovascular pathologies remain uncharacterized. This dissertation explores the various roles of FGF23 and vitamin D in monocytes and endothelial cells with a focus on CKD-induced cardiovascular co-morbidities.

CVD, particularly atherosclerosis, is initiated by systemic inflammation, endothelial dysfunction, and aberrant lipid profiles, with key players being monocyte/macrophage populations and the endothelium. The vitamin D system is well characterized in monocytes, acting in both antimicrobial and anti-inflammatory capacities. CKD is marked by chronic inflammation, which is also a key contributor to atherosclerosis. FGF23 is traditionally known for down regulating renal vitamin D synthesis. Given the connections between vitamin D and monocytes with CVD, we first sought to determine whether FGF23 had any effect on the vitamin D system in these cells. Here we demonstrate the ability for FGF23 to limit the immune properties of vitamin D in monocytes, and thus potentially contribute to the abnormal inflammatory patterns known to initiate CVD.

We next investigated the interactions between monocytes and endothelial cells in the context of CKD. Incubating co-cultures of human aortic endothelial cells and monocytes with FGF23 caused both phenotypic and functional changes in both cell types related to CVD. In the final two chapters, we focus on characterizing alternative functions of vitamin D in monocytes and endothelial cells. First, we demonstrate vitamin D indirectly facilitates monocyte iron sequestration related to anemia of CKD. Then, we also show that vitamin D exhibits antioxidative properties in endothelial cells that may play a beneficial in atherosclerotic plaque regression.

Taken together, we hope the work presented in this dissertation will provide new insights into the immune interactions that contribute to CKD pathogenesis or host protection. Understanding the interplay between the immune system and the endothelial microenvironment is a critical step to the eventual development of immunotherapies for CVD.