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Renal P2X receptors mediating pressure‐natriuresis, oxygenation and injury susceptibility (LB721)
Author(s) -
Menzies Robert,
Mullins John,
Bailey Matthew
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb721
Subject(s) - endocrinology , medicine , afferent arterioles , natriuresis , blood pressure , renal blood flow , losartan , kidney , kidney disease , renal medulla , renal function , angiotensin ii
Chronic kidney disease (CKD) affects an estimated 1 in 10 individuals and therefore presents a profound socioeconomic burden. The etiology of CKD is undoubtedly multifaceted, remaining largely elusive in spite of a significant focus of basic and translational research, resulting in fibrosis and renal function decline. We have developed models to investigate the pathology of CKD following over‐activation of the renin angiotensin system. In the Cyp1a1‐Ren2 transgenic rat hypertension causes renal injury, predominantly in the preglomerular vasculature. In this model renal injury is characterized by both blood pressure dependent (owing to the antihypertensive affect of Losartan), and blood pressure independent (amelioration of renal injury but not hypertension by spironolactone), mechanisms. Consomic/congenic strain variants identified angiotensin converting enzyme (Ace) as an important gene modifier. Comparative studies of F344 (susceptible) and Lewis (relatively protected) strains by renal microarray revealed the purinergic receptors P2x7 and P2x4 as further candidate modifiers. Gene and protein expression of these P2X receptors were both higher in F344 compared with Lewis. Immunohistochemistry localized P2X7 and P2X4 to the renal vascular endothelium, vasa recta and tubules: between strains the expression pattern only became architecturally distinct in the medulla. Renal functional studies indicated that F344, but not Lewis, responded to acute antagonism of P2X7 and P2X4. F344 showed a significant drop in blood pressure but maintained renal blood flow, indicative of tonic renal vasoconstriction by the vasa recta. Following chronic ANG II infusion into F344 rats, pressure‐natriuresis was impaired and there was a modest increase in blood pressure but no overt injury. Similarly, macrophage infiltration was not significantly increased. Blood oxygenation‐level dependent (BOLD) magnetic resonance imaging (MRI) of the kidney identified a decrease in renal R2* signal following P2X7 and P2X4 antagonism in ANG II infused F344 rats. Together these results suggest that P2X4/7 activation tonically suppress renal perfusion which impairs pressure‐natriuresis and reduces oxygenation. These effects are pro‐fibrotic and may underpin susceptibility to renal injury. Grant Funding Source : British Heart Foundation Centre of Research Excellence (CoRE) Award