title: Role of SRC family kinase in extracellular renal cyclic guanosine 3',5'-monophosphate- and pressure-induced natriuresis.
abstract: cGMP functions as an extracellular (paracrine) messenger acting at the renal proximal tubule and is an important modulator of pressure-natriuresis (P-N). The signaling pathway activated by cGMP in the tubule cell basolateral membrane remains unknown. We hypothesized that renal interstitial microinfusion of cGMP (50 nmol/kg per minute) or P-N would be accompanied by increased renal protein levels of phospho-Src (Tyr 416) and that the natriuresis would be decreased by Src inhibition. Renal interstitial cGMP-induced natriuresis was blocked by Src inhibitor PP2 (2.0±0.4 versus 0.5±0.01 μEq/g per minute; P<0.001). The inactive analog of PP2, PP3, had no effect on cGMP-induced natriuresis. SU6656, another Src inhibitor, also inhibited cGMP-induced natriuresis (2.0±0.4 versus 1.02±0.01 μEq/g per minute; P<0.001). Renal interstitial cGMP infusion increased phospho-Src protein levels 5.6-fold at 15 minutes and 6.8-fold at 30 minutes compared with vehicle infusion but returned toward basal levels after 60 minutes. PP2 also blunted P-N (3.1±0.1 versus 1.1±0.3 μEq/g per minute; P<0.01) despite a similar increase in blood pressure. PP3 had no effect on P-N. Phospho-Src protein levels increased during P-N in vehicle- (1.8-fold) and PP3-treated (2.1-fold) groups compared with the sham-operated group. PP2 blocked the pressure-induced increase in renal phospho-Src protein levels. PP2 had no effect on renal hemodynamics but decreased both fractional excretion of Na(+) and lithium. Both extracellular cGMP and increased renal perfusion pressure increased renal phospho-Src protein levels and induced natriuresis in an Src-dependent manner, demonstrating that Src is an important downstream signaling molecule for extracellular cGMP-induced natriuresis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1414, USA.
authors.forename: Nilberto R F
authors.initials: NR
authors.lastname: Nascimento
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Kemp
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Howell
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Cláudia F
authors.initials: CF
authors.lastname: Santos
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D009318:Natriuresis / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D012964:Sodium / Q000652:urine*; D013873:Thionucleotides / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D013873:Thionucleotides; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D012964:Sodium; D019061:src-Family Kinases; D006152:Cyclic GMP