Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone of putative bone origin that is elevated in patients with chronic kidney disease (CKD). The mechanisms responsible for elevations of FGF23 and its role in the pathogenesis of chronic kidney disease-mineral bone disorder (CKD-MBD) remain uncertain. We investigated the association between FGF23 serum levels and kidney disease progression, as well as the phenotypic features of CKD-MBD in a Col4a3 null mouse model of human autosomal-recessive Alport syndrome. These mice exhibited progressive renal failure, declining 1,25(OH)2D levels, increments in PTH and FGF23, late onset hypocalcemia and hyperphosphatemia, high-turnover bone disease, and increased mortality. Serum levels of FGF23 increased in the earliest stages of renal damage, prior to elevations in BUN and creatinine. FGF23 gene transcription in bone, however, did not increase until late-stage kidney disease, when serum FGF23 levels were exponentially elevated. Further evaluation of bone revealed trabecular osteocytes to be the primary cell source for FGF23 production in late-stage disease. Changes in FGF23 mirrored the rise in serum PTH and the decline in circulating 1,25(OH) 2D. The rise in PTH and FGF23 in Col4a3 null mice coincided with an increase in the urinary fractional excretion of phosphorus and a progressive decline in sodium-phosphate co-transporter gene expression in the kidney. Our findings suggest elevations of FGF23 in CKD to be an early marker of renal injury that increases prior to BUN and serum creatinine. An increased production of FGF23 by bone may not be responsible for early increments in FGF23 in CKD, but does appear to contribute to FGF23 levels in late-stage disease. Elevations in FGF23 and PTH coincide with an increase in urinary phosphate excretion that likely prevents the early onset of hyperphosphatemia in the face of increased bone turnover and a progressive decline in functional renal mass.

In vitro, monocyte 1␣-hydroxylase converts 25-hydroxyvitamin D [25(OH)D] to 1,25-dihydroxyvitamin D to regulate local innate immune responses, but whether 25(OH)D repletion affects vitamin D-responsive monocyte pathways in vivo is unknown. Here, we identified seven patients who had 25(OH)D insufficiency and were undergoing long-term hemodialysis and assessed changes after cholecalciferol and paricalcitol therapies in both vitamin D-responsive proteins in circulating monocytes and serum levels of inflammatory cytokines. Cholecalciferol therapy increased serum 25(OH)D levels four-fold, monocyte vitamin D receptor expression three-fold, and 24-hydroxylase expression; therapy decreased monocyte 1␣-hydroxylase levels. The CD16 ϩ "inflammatory" monocyte subset responded to 25(OH)D repletion the most, demonstrating the greatest increase in vitamin D receptor expression after cholecalciferol. Cholecalciferol therapy reduced circulating levels of inflammatory cytokines, including IL-8, IL-6, and TNF. These data suggest that nutritional vitamin D therapy has a biologic effect on circulating monocytes and associated inflammatory markers in patients with ESRD.

Mast cells (MC) are well known for their contribution to vascular inflammation and atherosclerosis. We have shown that MC proteases and histamine amplify lipopolysaccharide (LPS)-induced inflammatory responses in human coronary artery endothelial cells via stimulation of TLR4 expression. This study examined mRNA levels of COX1, COX2, TLR4 and eNOS in aortic tissues of MC-deficient (W/Wv) mice and wild type controls (WT) to gain insight into the role of MC in vascular pathophysiology. We also determined the effect of MC degranulation on gene expression in aortas 24 h after intraperitoneal injection of MC degranulation agent compound 48/80 (1 μg/g body wt). We found that, in comparison to WT, aortic tissues of W/Wv mice express lower levels of COX1, COX2, TLR4 and eNOS mRNA. Injection of compound 48/80 resulted in marked stimulation of expression of these genes in aortas of WT, but not in W/Wv mice, confirming the involvement of MC degranulation products in this process. To determine whether a deficiency of MC and/or decreased COX expression in W/Wv mice is associated with changes in prostanoid homoeostasis, the levels of prostacyclin and thromboxane A2 metabolites in urine samples were analyzed. The levels of 6-keto PGF1α and 11-dehydro TXB2 in 24 h urine of both genotypes were comparable when normalized for the volume and creatinine excretion. These results suggest that, although MC deficiency suppresses the expression of COX1 and COX2 genes in the vasculature, the systemic prostanoid homeostasis remains protected. (Supported by NIH R01-HL070101 and Carey Arthritis Fund)