Role of Src Family Kinase in Extracellular Renal Cyclic Guanosine 3′,5′-Monophosphate- and Pressure-Induced Natriuresis
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.
- kidney function
- blood pressure
- proximal tubule sodium reabsorption
- cyclic nucleotides
- extracellular fluid volume
- Received December 20, 2010.
- Revision received January 14, 2011.
- Accepted March 17, 2011.
- © 2011 American Heart Association, Inc.