Fibroblast growth factors (FGF) function during development and adult tissue homeostasis. Activity of these FGFs is modulated by three known secreted binding proteins (FGFBP or BP). Genome-wide association studies (GWAS) and familial hypertension studies have shown significant associations between the risk of hypertension and single nucleotide polymorphisms (SNPs) in different genes in the FGF pathway including BP1, FGF1 and FGFS. BP1 and FGF1 expression were also found elevated in kidney epithella and macrophages in subjects with hypertension. Whilst most of the known FGFs act locally, FGF19, 21 and 23 function as circulating factors in a hormone-like fashion and utilize the extracellular glucuronidase klotho as a co-receptor. Loss of klotho has been associated with defective FGF signaling and oxidative stress. We observed that conditional expression of the BP1 in mice caused a significant rise in blood pressure and a sensitization of resistance vessels to angiotensin II. Reversal by the superoxide dismutase mimetic Tempol suggests an essential role of oxidative stress. We also observed that BPS can function as a co- receptor for the circulating FGF19, 21 and 23 and impact their signaling. Thus, we hypothesize that BP1 and BPS interactions with FGF signaling modulates oxidative stress, blood pressure control and the sensitivity of glomerular afferent arterioles. To evaluate the contribution of endogenous BP1 expression, we have generated mice with a floxed BP1 gene for conditional deletion.
Under Aim 1 we plan to study the role endogenous BP1 expression during normal development and its contribution to the initiation and maintenance of disease caused by oxidative stress. BP1 will be conditionally deleted in the germline (Aim la), before induction of oxidative stress (Aim lb) and after chronic induction of oxidative stress (Aim 1c).
Under Aim 2 we will evaluate the contribution of BP1 expression to oxidative stress signaling by tissue specific deletion from kidney epithella (Aim 2a) and macrophages (Aim 2b).
Under Aim S we will evaluate the effect of BPS as a co-receptor for endocrine FGFs (FGF19, 21 and 23) and the impact of BPS on oxidative stress signaling in vivo and in vitro.
Alterations in, the FGF pathway appear to be significant drivers of chronic kidney disease as well as hypertension. FGF pathway activity is complex due to the high number of FGF ligands, receptors, binding proteins and co-receptors. Understanding the role of different contributors in the FGF pathway can reveal novel therapeutic targets in the treatment of chronic kidney disease as well as hypertension.
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