Interaction of COX-2 and nNOS in renin secretion

Summary

Principal Investigator: T Yang
Abstract: Elucidation of molecular pathways that determine renin secretion is of critical significance in understanding the role of renin-angiotensin system in the control of extracellular volume and blood pressure. Macula densa (MD) control of renin secretion is one of the key renin regulating pathways. In in vitro perfused juxtaglomerular apparatus (JGA), a reduction of NaCI concentration at the MD induced a marked increase in renin secretion. The mediators responsible for the MD control of renin secretion have been recognized to be prostaglandins and nitric oxide. In support of this notion, cyclooxygenase-2 (COX-2) and neuronal form of nitric oxide synthase (nNOS) are co-expressed in the MD, stimulated in parallel in various high renin states, and both being implicated to play a role in the control of renin secretion. However, the interaction of the two systems in the control of renin secretion is poorly defined. Our preliminary studies showed that plasma renin activity was significantly reduced in both COX-2 and nNOS knockout mice. In a recently established macula densa cell line, nitric oxide stimulated COX-2 expression and in turn the COX-2 product PGE2 inhibited nNOS expression that was further supported by the finding that nNOS expression was upregulated in the MD of COX-2 knockout mice. We hypothesize that the distinct interaction of COX-2 and nNOS in the MD cells forms a negative feedback loop that may play an important role in the tight control of renin secretion. The major goals of this proposal are to further delineate this feedback loop and to clarify its role in regulation of renin secretion with the following specific aims: 1) investigate the molecular mechanisms by which the COX-2 product PGE2 down-regulates nNOS expression in cultured macula densa cells in vitro; 2) investigate the molecular mechanisms by which the nNOS product nitric oxide stimulates COX-2 expression or activity in the cultured macula densa cells in vitro; and 3) further clarify the interrelationship among COX-2, renin and NOS isoforms in vivo.
Funding Period: 2003-09-30 - 2006-12-16
more information: NIH RePORT

Top Publications

  1. pmc Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention
    Hui Zhang
    Department of Internal Medicine and Pediatrics, University of Utah, Salt Lake City, UT 84132, USA
    Proc Natl Acad Sci U S A 102:9406-11. 2005
  2. ncbi Influence of genetic background and gender on hypertension and renal failure in COX-2-deficient mice
    Tianxin Yang
    National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Am J Physiol Renal Physiol 288:F1125-32. 2005
  3. ncbi Hypertonic induction of COX-2 in collecting duct cells by reactive oxygen species of mitochondrial origin
    Tianxin Yang
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA
    J Biol Chem 280:34966-73. 2005
  4. ncbi Nitric oxide stimulates COX-2 expression in cultured collecting duct cells through MAP kinases and superoxide but not cGMP
    Tianxin Yang
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA
    Am J Physiol Renal Physiol 291:F891-5. 2006
  5. ncbi Kidney-specific gene targeting: insight into thiazolidinedione-induced fluid retention
    Tianxin Yang
    Department of Internal Medicine, University of Utah, Salt Lake City, 84148, USA
    Nephrology (Carlton) 11:201-6. 2006
  6. ncbi Prostaglandin D2 inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in MDCK cells
    Aihua Zhang
    Division of Nephrology, University of Utah and VA Medical Center, Salt Lake City, UT 84148, USA
    Am J Physiol Renal Physiol 291:F1332-42. 2006
  7. ncbi Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion
    Zhanjun Jia
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT 84132, USA
    Circ Res 99:1243-51. 2006
  8. ncbi Microsomal prostaglandin E synthase-1 and blood pressure regulation
    T Yang
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84132, USA
    Kidney Int 72:274-8. 2007

Scientific Experts

  • T Yang
  • Aihua Zhang
  • Hui Zhang
  • Zheng Dong
  • Zhanjun Jia
  • Frank J Gonzalez
  • Donald E Kohan
  • Raoul D Nelson

Detail Information

Publications8

  1. pmc Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention
    Hui Zhang
    Department of Internal Medicine and Pediatrics, University of Utah, Salt Lake City, UT 84132, USA
    Proc Natl Acad Sci U S A 102:9406-11. 2005
    ..These findings demonstrate a PPARgamma-dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention...
  2. ncbi Influence of genetic background and gender on hypertension and renal failure in COX-2-deficient mice
    Tianxin Yang
    National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Am J Physiol Renal Physiol 288:F1125-32. 2005
    ....
  3. ncbi Hypertonic induction of COX-2 in collecting duct cells by reactive oxygen species of mitochondrial origin
    Tianxin Yang
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA
    J Biol Chem 280:34966-73. 2005
    ..We conclude that ROSs derived from mitochondria, but not NADPH oxidase, mediate the hypertonicity-induced phosphorylation of MAPK and the stimulation of COX-2 expression...
  4. ncbi Nitric oxide stimulates COX-2 expression in cultured collecting duct cells through MAP kinases and superoxide but not cGMP
    Tianxin Yang
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA
    Am J Physiol Renal Physiol 291:F891-5. 2006
    ..The stimulation was also significantly blocked by the SOD mimetic tempol. Thus we conclude that NO stimulates COX-2 expression in collecting duct cells through mechanisms involving MAP kinase and superoxide, but not cGMP...
  5. ncbi Kidney-specific gene targeting: insight into thiazolidinedione-induced fluid retention
    Tianxin Yang
    Department of Internal Medicine, University of Utah, Salt Lake City, 84148, USA
    Nephrology (Carlton) 11:201-6. 2006
    ..It is anticipated that over next few years this technique will be used by an increasing number of investigators for studying gene function in the kidney...
  6. ncbi Prostaglandin D2 inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in MDCK cells
    Aihua Zhang
    Division of Nephrology, University of Utah and VA Medical Center, Salt Lake City, UT 84148, USA
    Am J Physiol Renal Physiol 291:F1332-42. 2006
    ....
  7. ncbi Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion
    Zhanjun Jia
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT 84132, USA
    Circ Res 99:1243-51. 2006
    ..Overall, this study has characterized the natriuretic and antihypertensive role of mPGES-1 that likely contributes to blood pressure homeostasis...
  8. ncbi Microsomal prostaglandin E synthase-1 and blood pressure regulation
    T Yang
    Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84132, USA
    Kidney Int 72:274-8. 2007
    ..These mice also exhibit an exaggerated hypertensive response to angiotensin II infusion. Together, these results suggest that mPGES-1 may be an important physiological regulator of BP...