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Robert M Carey - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of dopamine d 1 and angiotensin type 2 receptor interaction in Natriuresis
    Hypertension, 2012
    Co-Authors: Shetal H Padia, Brandon A Kemp, Nancy L Howell, John J Gildea, Susanna R Keller, Robert M Carey
    Abstract:

    Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in Natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces Natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated Natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced Natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced Natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.

  • role of src family kinase in extracellular renal cyclic guanosine 3 5 monophosphate and pressure induced Natriuresis
    Hypertension, 2011
    Co-Authors: Nilberto Rf Nascimento, Brandon A Kemp, Nancy L Howell, John J Gildea, Claudia F Santos, Thurl E Harris, Robert M Carey
    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 P P + 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.

  • reinforcing feedback loop of renal cyclic guanosine 3 5 monophosphate and interstitial hydrostatic pressure in pressure Natriuresis
    Hypertension, 2009
    Co-Authors: David C Lieb, Brandon A Kemp, Nancy L Howell, John J Gildea, Robert M Carey
    Abstract:

    This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-Natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored Natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the Natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-Natriuresis.

John J Gildea - One of the best experts on this subject based on the ideXlab platform.

  • the synergistic roles of cholecystokinin b and dopamine d5 receptors on the regulation of renal sodium excretion
    PLOS ONE, 2016
    Co-Authors: Xiaoliang Jiang, John J Gildea, Wei Chen, Xing Liu, Zihao Wang, Yunpeng Liu, Robin A Felder, Pedro A Jose, Chuan Qin, Zhiwei Yang
    Abstract:

    Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote Natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The Natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the Natriuresis caused by gastrin was blocked by Sch23390 while the Natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.

  • mechanisms of dopamine d 1 and angiotensin type 2 receptor interaction in Natriuresis
    Hypertension, 2012
    Co-Authors: Shetal H Padia, Brandon A Kemp, Nancy L Howell, John J Gildea, Susanna R Keller, Robert M Carey
    Abstract:

    Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in Natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces Natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated Natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced Natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced Natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.

  • role of src family kinase in extracellular renal cyclic guanosine 3 5 monophosphate and pressure induced Natriuresis
    Hypertension, 2011
    Co-Authors: Nilberto Rf Nascimento, Brandon A Kemp, Nancy L Howell, John J Gildea, Claudia F Santos, Thurl E Harris, Robert M Carey
    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 P P + 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.

  • reinforcing feedback loop of renal cyclic guanosine 3 5 monophosphate and interstitial hydrostatic pressure in pressure Natriuresis
    Hypertension, 2009
    Co-Authors: David C Lieb, Brandon A Kemp, Nancy L Howell, John J Gildea, Robert M Carey
    Abstract:

    This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-Natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored Natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the Natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-Natriuresis.

Richard J. Johnson - One of the best experts on this subject based on the ideXlab platform.

  • impaired pressure Natriuresis resulting in salt sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney
    American Journal of Physiology-renal Physiology, 2013
    Co-Authors: Martha Franco, Richard J. Johnson, Edilia Tapia, Rocio Bautista, Ursino Pacheco, Jose Santamaria, Yasmir Quiroz, Bernardo Rodrigueziturbe
    Abstract:

    Immune cell infiltration of the kidney is a constant feature in salt-sensitive hypertension (SSHTN). We evaluated the relationship between the renal inflammation and pressure Natriuresis in the mod...

  • impaired pressure Natriuresis is associated with interstitial inflammation in salt sensitive hypertension
    Current Opinion in Nephrology and Hypertension, 2013
    Co-Authors: Bernardo Rodrigueziturbe, Martha Franco, Richard J. Johnson
    Abstract:

    PURPOSE OF REVIEW: Impairment of the pressure Natriuresis relationship is a central event in the pathogenesis of hypertension. Renal tubulointerstitial inflammation results in salt-sensitive hypertension and, until recently, the changes in pressure Natriuresis induced by renal inflammation received little attention. RECENT FINDINGS: Oxidative stress and increased intrarenal angiotensin II activity, in association with rarefaction and loss of peritubular vascular network, may be involved in the inflammation-induced blunting of the Natriuresis resulting from increments in renal perfusion pressure. SUMMARY: Here, we review the mechanisms for the impairment in pressure Natriuresis resulting from renal tubulointerstitial inflammation in reference to the normal physiologic mechanisms involved in this response.

  • hypothesis the role of acquired tubulointerstitial disease in the pathogenesis of salt dependent hypertension
    Kidney International, 1997
    Co-Authors: Richard J. Johnson, George F Schreiner
    Abstract:

    Hypothesis: The role of acquired tubulointerstitial disease in the pathogenesis of salt-dependent hypertension. We present a new hypothesis to explain the development of salt-dependent hypertension in humans. We propose that hypertension has two phases: an early phase in which elevations in blood pressure (BP) are mainly episodic and are mediated by a hyperactive sympathetic nervous or renin-angiotensin system, and a second phase in which BP is persistently elevated and that is primarily mediated by an impaired ability of the kidney to excrete salt (NaCl). We propose that the transition from the first phase to the second occurs as a consequence of catecholamine-induced elevations in BP that preferentially damage regions of the kidney (juxtamedullary and medullary regions) that do not autoregulate well to changes in renal perfusion pressure. The catecholamine response is associated with both an increase in peritubular capillary pressure and a reduction in perhjubular capillary plasma flow, resulting in injury to the peritubular capillaries with ischemia to the tubules and interstitium. The local injury triggers the release or activation (angiotensin II, adenosine, renal sympathetic nerves) or inhibition (nitric oxide, prostaglandins, dopamine) of vasoactive mediators that further augment ischemia and result in abnormal tubuloglomerular feedback and enhanced NaCl reabsorption. The peritubular capillary injury with rarefaction simultaneously blunts the pressure najriuresis mechanism. The combined effect of enhanced tubuloglomerular feedback and impaired pressure Natriuresis results in a defect in NaCl excretion which, on the exposure to salt, results in the development of persistent hypertension. Evidence is provided to suggest that this may be the major mechanism for the development of salt-dependent hypertension, and particularly for the hypertension associated with blacks, aging and obesity. Thus, essential hypertension may be a type of acquired tubulointerstitial renal disease.

Brandon A Kemp - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of dopamine d 1 and angiotensin type 2 receptor interaction in Natriuresis
    Hypertension, 2012
    Co-Authors: Shetal H Padia, Brandon A Kemp, Nancy L Howell, John J Gildea, Susanna R Keller, Robert M Carey
    Abstract:

    Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in Natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces Natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated Natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced Natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced Natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.

  • role of src family kinase in extracellular renal cyclic guanosine 3 5 monophosphate and pressure induced Natriuresis
    Hypertension, 2011
    Co-Authors: Nilberto Rf Nascimento, Brandon A Kemp, Nancy L Howell, John J Gildea, Claudia F Santos, Thurl E Harris, Robert M Carey
    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 P P + 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.

  • reinforcing feedback loop of renal cyclic guanosine 3 5 monophosphate and interstitial hydrostatic pressure in pressure Natriuresis
    Hypertension, 2009
    Co-Authors: David C Lieb, Brandon A Kemp, Nancy L Howell, John J Gildea, Robert M Carey
    Abstract:

    This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-Natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored Natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the Natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-Natriuresis.

Nancy L Howell - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of dopamine d 1 and angiotensin type 2 receptor interaction in Natriuresis
    Hypertension, 2012
    Co-Authors: Shetal H Padia, Brandon A Kemp, Nancy L Howell, John J Gildea, Susanna R Keller, Robert M Carey
    Abstract:

    Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in Natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces Natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated Natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced Natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced Natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.

  • role of src family kinase in extracellular renal cyclic guanosine 3 5 monophosphate and pressure induced Natriuresis
    Hypertension, 2011
    Co-Authors: Nilberto Rf Nascimento, Brandon A Kemp, Nancy L Howell, John J Gildea, Claudia F Santos, Thurl E Harris, Robert M Carey
    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 P P + 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.

  • reinforcing feedback loop of renal cyclic guanosine 3 5 monophosphate and interstitial hydrostatic pressure in pressure Natriuresis
    Hypertension, 2009
    Co-Authors: David C Lieb, Brandon A Kemp, Nancy L Howell, John J Gildea, Robert M Carey
    Abstract:

    This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-Natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored Natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the Natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-Natriuresis.