Role of Src Family Kinase in Extracellular Renal Cyclic Guanosine 3′,5′-Monophosphate- and Pressure-Induced Natriuresis

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 58; no. 1; pp. 107 - 113
• Main Authors: Nascimento, Nilberto R.F, Kemp, Brandon A, Howell, Nancy L, Gildea, John J, Santos, Cláudia F, Harris, Thurl E, Carey, Robert M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-07-2011; Lippincott Williams & Wilkins
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cyclic GMP - analogs & derivatives; Cyclic GMP - pharmacology; Disease Models, Animal; Extracellular Fluid - metabolism; Female; Hypertension - metabolism; Hypertension - physiopathology; Kidney - drug effects; Kidney - metabolism; Medical sciences; Natriuresis - drug effects; Natriuresis - physiology; Rats; Rats, Sprague-Dawley; Signal Transduction; Sodium - urine; src-Family Kinases - metabolism; Thionucleotides - pharmacology; Hypertension; kidney function; 3',5'-GMP; Cardiovascular disease; Reabsorption; proximal tubule sodium reabsorption; extracellular fluid volume; c-Src; Sodium; C-Onc gene; cyclic nucleotides; Arterial pressure; Blood pressure
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.168708

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.