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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL068686-11A1
Application #
8458216
Study Section
Special Emphasis Panel (ZHL1-PPG-S (O1))
Project Start
Project End
Budget Start
2013-02-15
Budget End
2014-01-31
Support Year
11
Fiscal Year
2013
Total Cost
$325,816
Indirect Cost
$117,889
Name
Georgetown University
Department
Type
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Pei, Lei; Solis, Glenn; Nguyen, Mien T X et al. (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509-18
Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34
Jose, Pedro A; Yang, Zhiwei; Zeng, Chunyu et al. (2016) The importance of the gastrorenal axis in the control of body sodium homeostasis. Exp Physiol 101:465-70
Sanada, H; Yoneda, M; Yatabe, J et al. (2016) Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. Pharmacogenomics J 16:3-9
Zhang, Gensheng; Wang, Qiaoling; Zhou, Qin et al. (2016) Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway. Kidney Blood Press Res 41:129-38
Jose, Pedro A; Felder, Robin A; Yang, Zhiwei et al. (2016) Gastrorenal Axis. Hypertension 67:1056-63
Li, Lingli; Lai, En Yin; Wellstein, Anton et al. (2016) Differential effects of superoxide and hydrogen peroxide on myogenic signaling, membrane potential, and contractions of mouse renal afferent arterioles. Am J Physiol Renal Physiol 310:F1197-205
Zhang, Yanrong; Jiang, Xiaoliang; Qin, Chuan et al. (2016) Dopamine D2 receptors' effects on renal inflammation are mediated by regulation of PP2A function. Am J Physiol Renal Physiol 310:F128-34
Konkalmatt, Prasad R; Asico, Laureano D; Zhang, Yanrong et al. (2016) Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight 1:
Wang, Renjun; Huang, Qian; Zhou, Rui et al. (2016) Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circ Heart Fail 9:e002261

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