Blood Pressure Regulation: Novel Roles for the Kidney

Summary

Principal Investigator: Pablo A Ortiz
Abstract: This is a revised Program Project Grant, the central theme is that "endocrine, paracrine and autoerine factors produced by the epithelial, vascular smooth muscle, endothelial and interstitial cells play an important role in regulating salt and water excretion by the kidney, and thus blood pressure, by altering renal hempdynamics, changing NaCI reabsorption and mediating cross-talk between cells." The central hypothesis to be tested is that blood pressure regulation by the kidney occurs via integration of the actions of prch and anti-hypertensive agents on nephron transport, renal vascular resistance, release of renal hormones and cross-talk between epithelial and vascular cells. Defects in the integration process and/or actions of pro- and anti-hypertensive agents lead to renal dysfunction, salt retention and hypertension. This hypothesis will be tested in four projects that break new ground in our understanding of how the kidney regulates blood pressure. Project 1 will study whether increasing luminal flow in the thick ascending limb stimulates nitric oxide (NO) production by NO synthase 3, the signaling cascades involved, the effects of flow-induced NO on NaCI reabsorption, and whether a defective response to flow-stimulated NO production enhances sait retention and promotes salt-sensitive hypertension. Project 2 will test whether NO inhibits thick ascending limb NaCI reabsorption by activating cGMP-stimulated phosphodiesterase 2 (PDE2), reducing cAMP, and thus decreasing Na/K/2CI cotransport. It will also test in Dahl salt-sensitive rats whether a reduction in NOinduced inhibition of NaCI reabsorption and hypertension is caused by diminished PDE2 activity and enhanced cGMP degradation by phosphodiesterase 5. Project 3 will test whether heme oxygenases in the macula densa produce carbon monoxide (CO) and biliverdin, which act synergistically and in an autocrine manner to inhibit tubuloglomeailar feedback. It will also test whether CO acts by stimulating cGMP which inhibits Na/K/2CI cotransport, and blocks ATP release and biliverdin acts by decreasing superoxide, thereby increasing NO. Project 4 will test whether increased extracellular Ca inhibits renin release by activating Ca sensing receptors on juxtaglomerular cells which increases intracellular Ca and reduces cAMP production by inhibiting adenylyl cyclase-V and stimulating phosphodiesterase 1. These studies will be performed in vitro at the subcellular, cellular, and isolated tissue levels and in vivo using both acute and chronic models, and genetically manipulated mice. The four projects will be supported by three core units (Administrative, Molecular Biology and Analytical, and Imaging) that will facilitate the scientific effort. The Program Project Grant will provide integration of our efforts, continued collaboration and shared ideas and expertise. Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs.
Funding Period: 2009-04-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Akt1 mediates purinergic-dependent NOS3 activation in thick ascending limbs
    Guillermo B Silva
    Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 W Grand Boulevard, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 297:F646-52. 2009
  2. pmc The influence of extracellular and intracellular calcium on the secretion of renin
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department Internal Medicine, Henry Ford Hospital, 7121 E and R Bldg, 2799 W Grand Blvd, Detroit, MI 48202, USA
    Pflugers Arch 465:59-69. 2013
  3. pmc Tumor necrosis factor α decreases nitric oxide synthase type 3 expression primarily via Rho/Rho kinase in the thick ascending limb
    Vanesa D Ramseyer
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202 2689, USA
    Hypertension 59:1145-50. 2012
  4. pmc Parathyroid hormone-related protein stimulates plasma renin activity via its anorexic effects on sodium chloride intake
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA
    Am J Physiol Endocrinol Metab 303:E457-63. 2012
  5. pmc Angiotensin II type 2 receptor-mediated inhibition of NaCl absorption is blunted in thick ascending limbs from Dahl salt-sensitive rats
    Nancy J Hong
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Hypertension 60:765-9. 2012
  6. pmc Angiotensin II stimulates superoxide production in the thick ascending limb by activating NOX4
    Katherine J Massey
    Hypertension and Vascular Research Division, Dept of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Cell Physiol 303:C781-9. 2012
  7. pmc Parathyroid hormone stimulates juxtaglomerular cell cAMP accumulation without stimulating renin release
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F1157-65. 2012
  8. pmc NADPH oxidase 4 mediates flow-induced superoxide production in thick ascending limbs
    Nancy J Hong
    Hypertension and Vascular Research Div, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F1151-6. 2012
  9. pmc β-Adrenergic receptor stimulation increases surface NKCC2 expression in rat thick ascending limbs in a process inhibited by phosphodiesterase 4
    Mohammed Z Haque
    Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F1307-14. 2012
  10. ncbi Hyperphosphorylation of Na-K-2Cl cotransporter in thick ascending limbs of Dahl salt-sensitive rats
    Gustavo R Ares
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Hypertension 60:1464-70. 2012

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013

Detail Information

Publications35

  1. pmc Akt1 mediates purinergic-dependent NOS3 activation in thick ascending limbs
    Guillermo B Silva
    Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 W Grand Boulevard, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 297:F646-52. 2009
    ..In vivo transduction of TALs with a dominant-negative Akt1 significantly decreased ATP-induced NO by 88 +/- 6%. We concluded that ATP increases NOS3-derived NO via Akt1 activation in the TAL...
  2. pmc The influence of extracellular and intracellular calcium on the secretion of renin
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department Internal Medicine, Henry Ford Hospital, 7121 E and R Bldg, 2799 W Grand Blvd, Detroit, MI 48202, USA
    Pflugers Arch 465:59-69. 2013
    ....
  3. pmc Tumor necrosis factor α decreases nitric oxide synthase type 3 expression primarily via Rho/Rho kinase in the thick ascending limb
    Vanesa D Ramseyer
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202 2689, USA
    Hypertension 59:1145-50. 2012
    ..These data suggest that some of the beneficial effects of ROCK inhibitors in hypertension could be attributed to the mitigation of TNF-α-induced reduction in NOS3 expression...
  4. pmc Parathyroid hormone-related protein stimulates plasma renin activity via its anorexic effects on sodium chloride intake
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA
    Am J Physiol Endocrinol Metab 303:E457-63. 2012
    ..3% NaCl in the drinking water had no effect on PRA in normal rats. Thus, our data support the hypothesis that PTHrP increases PRA via its anorexic effects, reducing NaCl intake and causing NaCl restriction...
  5. pmc Angiotensin II type 2 receptor-mediated inhibition of NaCl absorption is blunted in thick ascending limbs from Dahl salt-sensitive rats
    Nancy J Hong
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Hypertension 60:765-9. 2012
    ..Impaired AT(2)R-mediated signaling in TALs could contribute to the Na retention associated with salt-sensitive hypertension...
  6. pmc Angiotensin II stimulates superoxide production in the thick ascending limb by activating NOX4
    Katherine J Massey
    Hypertension and Vascular Research Division, Dept of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Cell Physiol 303:C781-9. 2012
    ..We concluded that NOX4 is the main catalytic isoform of NADPH oxidase that contributes to ANG II-stimulated O(2)(-) production by TALs...
  7. pmc Parathyroid hormone stimulates juxtaglomerular cell cAMP accumulation without stimulating renin release
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F1157-65. 2012
    ..29 ± 0.08 ng ANG I·mg prot(-1)·h(-1) (P < 0.01). Thus PTH increases JG cell cAMP via non-calcium-sensitive adenylate cyclases without affecting renin release. These data suggest compartmentalization of cAMP signaling in JG cells...
  8. pmc NADPH oxidase 4 mediates flow-induced superoxide production in thick ascending limbs
    Nancy J Hong
    Hypertension and Vascular Research Div, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F1151-6. 2012
    ..In TALs transduced with Nox1 siRNA, flow-induced O(2)(-) was 82 ± 7 AU/s. We conclude that Nox4 mediates flow-induced O(2)(-) production in TALs...
  9. pmc β-Adrenergic receptor stimulation increases surface NKCC2 expression in rat thick ascending limbs in a process inhibited by phosphodiesterase 4
    Mohammed Z Haque
    Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F1307-14. 2012
    ..We concluded that β-adrenergic receptor stimulation enhances surface NKCC2 expression in the THALs via PKA and PDE4 blunts this effect...
  10. ncbi Hyperphosphorylation of Na-K-2Cl cotransporter in thick ascending limbs of Dahl salt-sensitive rats
    Gustavo R Ares
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Hypertension 60:1464-70. 2012
    ..These differences in NKCC2 may be, in part, responsible for higher NKCC2 activity and abnormally enhanced thick ascending limb NaCl reabsorption in DSS rats...
  11. pmc Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor
    M Cecilia Ortiz-Capisano
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 304:F248-56. 2013
    ..001). We conclude stimulating JG cell CaSR activates G(q), initiating the PLC/IP(3) pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition...
  12. pmc Tumor necrosis factor-α: regulation of renal function and blood pressure
    Vanesa D Ramseyer
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 304:F1231-42. 2013
    ..It also mediates organ damage by stimulating immune cell infiltration and cell death. Here we will summarize the available findings and attempt to provide plausible explanations for such discrepancies...
  13. pmc Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway
    M Cecilia Ortiz-Capisano
    Henry Ford Hospital, Dept of Medicine, Hypertension and Vascular Research Division, 7088 E and R Bldg, 2799 W Grand Blvd, Detroit, MI 48202
    Am J Physiol Renal Physiol 305:F1209-19. 2013
    ..Thus A1R activation results in a calcium-dependent inhibition of renin release via TRPC-mediated calcium entry, but A2 receptors do not regulate renin release. ..
  14. pmc Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and β-adrenergic activity
    Douglas K Atchison
    Dept of Internal Medicine, Hypertension and Vascular Research Div, Henry Ford Hospital, 7121 E and R Bldg, 2799 W Grand Blvd, Detroit, MI 48202
    Am J Physiol Renal Physiol 305:F1109-17. 2013
    ..Cyclooxygenase-2 inhibition had no effect on calcitriol-stimulated PRA. Our data demonstrate that vitamin D increases PRA independently of plasma Ca(2+) via hypercalciuria, polyuria, hypovolemia, and increased β-adrenergic activity. ..
  15. pmc Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback
    YiLin Ren
    Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
    Hypertension 59:1139-44. 2012
    ..Our results will lead to a better understanding of the mechanisms that control the renal microcirculation...
  16. pmc ATP mediates flow-induced NO production in thick ascending limbs
    Pablo D Cabral
    Hypertension and Vascular Research Div, Dept of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 303:F194-200. 2012
    ..We conclude that ATP mediates flow-induced NO production in the thick ascending limb likely via activation of P2Y receptors in the luminal and P2X receptors in the basolateral membrane...
  17. pmc cAMP stimulates apical exocytosis of the renal Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in the thick ascending limb: role of protein kinase A
    Paulo S Caceres
    Hypertension and Vascular Research Division, Henry Ford Hospital, Wayne State University, Detroit, Michigan 48202, USA
    J Biol Chem 284:24965-71. 2009
    ..We conclude that cAMP stimulates steady-state apical surface NKCC2 by stimulating exocytic insertion and that this process is highly dependent on PKA but not Epac...
  18. pmc Rac1 mediates NaCl-induced superoxide generation in the thick ascending limb
    Guillermo B Silva
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Mchigan 48202, USA
    Am J Physiol Renal Physiol 298:F421-5. 2010
    ..33 +/- 0.04 vs. 0.81 +/- 0.17 nmol O(2)(-) x min(-1) x mg protein(-1), n = 6, P < 0.05). We concluded that physiological increases in NaCl stimulate TAL O(2)(-) generation by activating Rac1...
  19. pmc PKC-alpha mediates flow-stimulated superoxide production in thick ascending limbs
    Nancy J Hong
    Department of Internal Medicine, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 298:F885-91. 2010
    ..001; n = 6). We concluded that flow stimulates net O(2)(-) production in thick ascending limbs via PKC-alpha-mediated activation of NADPH oxidase...
  20. pmc Nitric oxide produced by endothelial nitric oxide synthase promotes diuresis
    Jazmin M Pérez-Rojas
    Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Regul Integr Comp Physiol 298:R1050-5. 2010
    ..We conclude that 1) NO produced by NOS 3 promotes water and Na(+) excretion and 2) the renal epithelial actions of NO produced by NOS 3 supersede the systemic and renal vascular actions...
  21. pmc Angiotensin II stimulates thick ascending limb NO production via AT(2) receptors and Akt1-dependent nitric-oxide synthase 3 (NOS3) activation
    Marcela Herrera
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA
    J Biol Chem 285:14932-40. 2010
    ..01). Akt inhibition prevented NOS3 phosphorylation. We concluded that Ang II enhances TAL NO production via activation of AT(2) and Akt1-dependent phosphorylation of NOS3 at serines 1177 and 633...
  22. pmc Acute activation of the calcium-sensing receptor inhibits plasma renin activity in vivo
    Douglas K Atchison
    Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA
    Am J Physiol Regul Integr Comp Physiol 299:R1020-6. 2010
    ..In conclusion, calcium-sensing receptors are expressed in juxtaglomerular cells in vivo, and acute activation of these receptors with cinacalcet inhibits PRA in anesthetized rats, independent of parathyroid hormone...
  23. pmc Shear stress increases nitric oxide production in thick ascending limbs
    Pablo D Cabral
    Hypertension and Vascular Research Div, Dept of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 299:F1185-92. 2010
    ..We concluded that shear stress rather than pressure, stretch, or ion delivery mediates flow-induced stimulation of NO by NOS 3 in thick ascending limbs...
  24. pmc High salt differentially regulates surface NKCC2 expression in thick ascending limbs of Dahl salt-sensitive and salt-resistant rats
    Mohammed Ziaul Haque
    Department of Internal Medicine, Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 300:F1096-104. 2011
    ..We conclude that HS intake causes different effects on surface NKCC2 in SS and SR rats. Our data suggest that enhanced surface NKCC2 in SS rats might contribute to enhanced NaCl reabsorption in SS rats during HS intake...
  25. pmc Luminal flow regulates NO and O2(-) along the nephron
    Pablo D Cabral
    Hypertension and Vascular Research Div, Dept of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 300:F1047-53. 2011
    ..Although much progress has been made on this subject in the last few years, there are still many unanswered questions...
  26. pmc Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the α1 or α2 Na-K-ATPase ouabain-binding site
    John N Lorenz
    Dept of Molecular and Cellular Physiology, Univ of Cincinnati College of Medicine, OH 45267 0576, USA
    Am J Physiol Renal Physiol 301:F615-21. 2011
    ..In addition, use of a polyurethane cuff to constrict the renal artery provides a reliable method for producing 2K1C hypertension in mice...
  27. pmc Hypercalcemia reduces plasma renin via parathyroid hormone, renal interstitial calcium, and the calcium-sensing receptor
    Douglas K Atchison
    Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
    Hypertension 58:604-10. 2011
    ..001) compared with intact rats. Our data suggest that acute hypercalcemia inhibits PRA via the calcium-sensing receptor because of parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5...
  28. pmc Molecular regulation of NKCC2 in the thick ascending limb
    Gustavo R Ares
    Hypertension and Vascular Research Division, Dept of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
    Am J Physiol Renal Physiol 301:F1143-59. 2011
    ..The focus of this review is to summarize recent data regarding NKCC2 regulation and discuss their potential implications in physiological control of TAL function, renal physiology, and blood pressure regulation...
  29. pmc Resveratrol induces acute endothelium-dependent renal vasodilation mediated through nitric oxide and reactive oxygen species scavenging
    Kevin L Gordish
    Dept Internal Medicine, Hypertension and Vascular Research Div, Henry Ford Hospital, 7088 E and R Bldg, 2799 W Grand Blvd, Detroit, MI 48202
    Am J Physiol Renal Physiol 306:F542-50. 2014
    ..We conclude intravenous resveratrol acts as an acute renal vasodilator, partially mediated by increased NO production/NO bioavailability and superoxide scavenging but not by inducing vasodilatory cyclooxygenase products. ..

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..