title: Enhanced tubuloglomerular feedback in mice with vascular overexpression of A1 adenosine receptors.
abstract: Adenosine 1 receptors (A1AR) in the kidney are expressed in the vasculature and the tubular system. Pharmacological inhibition or global genetic deletion of A1AR causes marked reductions or abolishment of tubuloglomerular feedback (TGF) responses. To assess the function of vascular A1AR in TGF, we generated transgenic mouse lines in which A1AR expression in smooth muscle was augmented by placing A1AR under the control of a 5.38-kb fragment of the rat smooth muscle alpha-actin promoter and first intron (12). Two founder lines with highest expression in the kidney [353 +/- 42 and 575 +/- 43% compared with the wild type (WT)] were used in the experiments. Enhanced expression of A1AR at the expected site in these lines was confirmed by augmented constrictor responses of isolated afferent arterioles to administration of the A1AR agonist N6-cyclohexyladenosine. Maximum TGF responses (0-30 nl/min flow step) were increased from 8.4 +/- 0.9 mmHg in WT (n = 21) to 14.2 +/- 0.7 mmHg in A1AR-transgene (tg) 4 (n = 22; P < 0.0001), and to 12.6 +/- 1.2 mmHg in A1AR-tg7 (n = 12; P < 0.02). Stepwise changes in perfusion flow caused greater numerical TGF responses in A1AR-tg than WT in all flow ranges with differences reaching levels of significance in the intermediate flow ranges of 7.5-10 and 10-15 nl/min. Proximal-distal single-nephron glomerular filtration rate (SNGFR) differences (free-flow micropuncture) were also increased in A1AR-tg, averaging 6.25 +/- 1.5 nl/min compared with 2.6 +/- 0.51 nl/min in WT (P = 0.034). Basal plasma renin concentrations as well as the suppression of renin secretion after volume expansion were similar in A1AR-tg and WT mice, suggesting lack of transgene expression in juxtaglomerular cells. These data indicate that A1AR expression in vascular smooth muscle cells is a critical component for TGF signaling and that changes in renal vascular A1AR expression may determine the magnitude of TGF responses.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Oppermann
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.forename: En Yin
authors.initials: EY
authors.lastname: Lai
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisner
authors.forename: Lingli
authors.initials: L
authors.lastname: Li
authors.forename: Yuning
authors.initials: Y
authors.lastname: Huang
authors.forename: Diane
authors.initials: D
authors.lastname: Mizel
authors.forename: Justyna
authors.initials: J
authors.lastname: Fryc
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
authors.forename: Josephine
authors.initials: J
authors.lastname: Briggs
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Hayo
authors.initials: H
authors.lastname: Castrop
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005246:Feedback / Q000502:physiology*; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis* / Q000235:genetics; D012083:Renin / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000502:physiology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D018076:DNA, Complementary; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D016211:Transforming Growth Factor alpha; D012083:Renin