Skip to main content

Advertisement

Log in

Differential regulation of renin and Cox-2 expression in the renal cortex of C57Bl/6 mice

  • Renal Function, Body Fluids
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Based on the controversy about the relevance of cyclooxygenase-2 (Cox-2)-derived prostanoids from the macula densa for the control of the renin system, this study aimed to determine the interrelation between Cox-2 and renin expression in the mouse kidney. In control mice renin mRNA was readily detectable whilst renocortical Cox-2 mRNA abundance was at the detection limit of the RNase protection assay and no specific signals for Cox-2 were obtained by in situ hybridization or Western blot analysis. Experimental maneuvers such as low-salt diet, treatment with loop diuretics or angiotensin I converting enzyme inhibitors clearly increased renin mRNA abundance up to sevenfold, but under none of these conditions renocortical Cox-2 mRNA levels were significantly changed. Moreover, the strong stimulation of renin expression by angiotensin I-converting enzyme inhibition was not changed by the cyclooxygenase inhibitor ibuprofen, which in turn clearly lowered tissue prostanoid content. Our data suggest a marked divergence of renin and Cox-2 expression in the kidney cortex of C57Bl/6 mice with no clear evidence for a role of Cox-2-derived prostanoids from the macula densa in the regulation of renin expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Castrop H, Kammerl M, Mann B, Jensen BL, Kramer BK, Kurtz A(2000) Cyclooxygenase 2 and neuronal nitric oxide synthase expression in the renal cortex are not interdependent in states of salt deficiency. Pflugers Arch 441:235–240

    CAS  PubMed  Google Scholar 

  2. Castrop H, Schweda F, Schumacher K, Wolf K, Kurtz A(2001) Role of renocortical cyclooxygenase-2 for renal vascular resistance and macula densa control of renin secretion. J Am Soc Nephrol12:867–874

    Google Scholar 

  3. Castrop H, Klar J, Wagner C, Hocherl K, Kurtz A (2003) General inhibition of renocortical cyclooxygenase-2 expression by the renin-angiotensin system. Am J Physiol 284:F518–524

    Google Scholar 

  4. Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, Harris RC(1999) Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest 103:953–961

    CAS  PubMed  Google Scholar 

  5. Cheng HF, Wang JL, Zhang MZ, McKanna JA, Harris RC(2000) Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride. J Clin Invest 106:681–688

    CAS  PubMed  Google Scholar 

  6. Cheng HF, Wang JL, Zhang MZ, Wang SW, McKanna JA, Harris RC (2001) Genetic deletion of Cox-2 prevents increased renin expression in response to ACE inhibition. Am J Physiol 280:F449–F456

    CAS  Google Scholar 

  7. Cheng HF, Wang CJ, Moeckel GW, Zhang MZ, McKanna JA, Harris RC.(2002) Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension. Kidney Int 62:929–939

    CAS  PubMed  Google Scholar 

  8. Cheng HF, Wang SW, Zhang MZ, McKanna JA, Breyer R, Harris RC (2002) Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1. Am J Physiol 283:R638–R646

    CAS  Google Scholar 

  9. Chomczynski P, Sacchi N(1987) Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 62:156–159

    Article  Google Scholar 

  10. DeWitt DL, El-Harith EA, Kraemer SA, Andrews MJ, Yao EF, Armstrong RL, Smith WL (1990) The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthase. J Biol Chem 265:5192–5198

    CAS  PubMed  Google Scholar 

  11. Harding P, Carretero OA, Beierwaltes WH.(2000) Chronic cyclooxygenase-2 inhibition blunts low-sodium-stimulated renin without changing haemodynamics. J Hypertens 18:1107–1113

    CAS  PubMed  Google Scholar 

  12. Harris RC (2003) Interactions between Cox-2 and the renin-angiotensin system in the kidney. Acta Physiol Scand 177:423–427

    CAS  PubMed  Google Scholar 

  13. Harris RC, Breyer MD (2001) Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol 281:F1–F11

    CAS  PubMed  Google Scholar 

  14. Harris RC, McKanna JA, Akai Y, Jacobson HR, Duboi RN, Breyer MD(1994) Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94:2504–2510

    CAS  PubMed  Google Scholar 

  15. Harris RC, Cheng H, Wang J, Zhang M, McKanna JA (2000) Interactions of the renin-angiotensin system and neuronal nitric oxide synthase in regulation of cyclooxygenase-2 in the macula densa. Acta Physiol Scand 168:47–51

    CAS  PubMed  Google Scholar 

  16. Hartner A, Goppelt-Struebe M, Hilgers KF (1998) Coordinate expression of cyclooxygenase-2 and renin in the rat kidney in hypertension. Hypertension 31:201

    CAS  PubMed  Google Scholar 

  17. Hocherl K, Wolf K, Castrop H, Ittner KP, Bucher M, Kees F, Grobecker HF, Kurtz A (2001) Renocortical expression of renin and of cyclooxygenase-2 in response to angiotensin II AT1 receptor blockade is closely coordinated but not causally linked. Pflugers Arch 442:821–827

    CAS  PubMed  Google Scholar 

  18. Hocherl K, Kammerl MC, Schumacher K, Endemann D, Grobecker HF, Kurtz A (2002) Role of prostanoids in regulation of the renin-angiotensin-aldosterone system by salt intake. Am J Physiol 283:F294–F301

    CAS  Google Scholar 

  19. Ichitani Y, Holmberg K, Maunsbach AB, Haeggstrom JZ, Samuelsson B, De Witt D, Hokfelt T (2001) Cyclooxygenase-1 and cyclooxygenase-2 expression in rat kidney and adrenal gland after stimulation with systemic lipopolysaccharide: in situ hybridization and immunocytochemical studies. Cell Tissue Res 303:235–245

    CAS  PubMed  Google Scholar 

  20. Igarashi P, Vanden Heuvel GB, Payne JA, Forbush B III (1995) Cloning, embryonic expression, and alternative splicing of a kidney-specific Na-K-Cl cotransporter. Am J Physiol 69:F405–F418

    Google Scholar 

  21. Ito M, Oliverio MJ, Mannon PJ, Best CF, Maeda N, Smithies O, Coffman TM (1995) Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA 92:3521–3525

    CAS  PubMed  Google Scholar 

  22. Jensen BL; Kurtz A (1997) Differential regulation of renal cyclooxygenase mRNA by dietary salt intake. Kidney Int 52:1242–9

    CAS  PubMed  Google Scholar 

  23. Kammerl MC, Nusing RM, Seyberth HW, Riegger GA, Kurtz A, Kramer BK (2001) Inhibition of cyclooxygenase-2 attenuates urinary prostanoid excretion without affecting renal renin expression. Pflugers Arch 442:842–847

    CAS  PubMed  Google Scholar 

  24. Khan KN, Venturini CM, Bunch RT, Brassard JA, Koki AT, Morris DL, Trump BF, Maziasz TJ, Alden CL (1998) Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol 26:612–620

    CAS  PubMed  Google Scholar 

  25. Kihara M, Umemura S, Sugaya T, Toya Y, Yabana M, Kobayashi S, Tamura K, Kadota T, Kishida R, Murakami K, Fukamizu A, Ishii M (1998) Expression of neuronal type nitric oxide synthase and renin in the juxtaglomerular apparatus of angiotensin type-1a receptor gene-knockout mice. Kidney Int 53:1585–1593

    CAS  PubMed  Google Scholar 

  26. Kim WS, Murakami K, Nakayama K (1989) Nucleotide sequence of a cDNA coding for mouse Ren1 gene. Nucleic Acids Res 17:9480

    CAS  PubMed  Google Scholar 

  27. Komhoff M, Grone HJ, Klein T, Seyberth HW, Nusing RM (1997) Localization of cyclooxygenase-1 and −2 in adult and fetal human kidney: implication for renal function. Am J Physiol 272F460–F468

  28. Komhoff M, Jeck ND, Seyberth HW, Grone HJ, Nusing RM, Breyer MD (2000) Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int 58:2420–2424

    CAS  PubMed  Google Scholar 

  29. Komhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, Breyer MD (2000) Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int 57:414–422

    CAS  PubMed  Google Scholar 

  30. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (1991) TIS10, a phorbol ester tumor promotor-inducible mRNA from swiss cells, encodes a novel prostaglandin synthase/cyclooxygenase homologous. J Biol Chem 266:12866–12872

    CAS  PubMed  Google Scholar 

  31. Laemmli UK (1977) Cleavage of structural proteins during assembly of the head of bacteriophage T4. Nature 227:680–685

    Google Scholar 

  32. Mann B, Hartner A, Jensen BL, Hilgers KF, Hocherl K, Kramer BK, Kurtz A (2001) Acute upregulation of Cox-2 by renal artery stenosis. Am J Physiol 280:F119–F125

    CAS  Google Scholar 

  33. Mann B, Hartner A, Jensen BL, Kammerl M, Kramer BK, Kurtz A (2001) Furosemide stimulates macula densa cyclooxygenase-2 expression in rats. Kidney Int 59:62–68

    CAS  PubMed  Google Scholar 

  34. Meade EA, McIntyre TM, Zimmerman GA, Prescott SM (1999) Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. J Biol Chem 274:8328–8334

    CAS  PubMed  Google Scholar 

  35. Nantel F, Meadows E, Denis D, Connolly B, Metters KM, Giaid A (1999) Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly. FEBS Lett 475–477

  36. Norwood VF, Morham SG, Smithies O (2000) Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice. Kidney Int 58:2291–300

    Article  CAS  PubMed  Google Scholar 

  37. Ogura T, Yokoyama T, Fujisawa Y, Esumi H (1993) Structural diversity of neuronal nitric oxide synthase mRNA in the nervous system. Biochem Biophys Res Commun 193:1014–1022

    CAS  PubMed  Google Scholar 

  38. Paik JH, Ju JH, Lee JY, Boudreau MD, Hwang DH (2000) Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways. J Biol Chem 275:28173–179

    CAS  PubMed  Google Scholar 

  39. Pluskal MG, Przekop MB, Kavonian MR (1986) Immobilon PVDF transfer membrane. A new membrane substrate for Western blotting of proteins. Biotechniques 4:272–283

    CAS  Google Scholar 

  40. Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nusing RM, Seyberth HW, Komhoff M (2002) Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int 62:253–260

    CAS  PubMed  Google Scholar 

  41. Schafer JA, Watkins ML, Li L, Herter P, Haxelmans S, Schlatter E (1997) A simplified method for isolation of large numbers of defined nephron segments. Am J Physiol 273:F650–F657

    PubMed  Google Scholar 

  42. Schricker K, Hegyi I, Hamann M, Kaissling B, Kurtz A (1993) Endothelium derived NO stimulates pressure dependent renin release in conscious rats. Am J Physiol 264:F943–F947

    PubMed  Google Scholar 

  43. Schweda F, Wagner C, Kramer BK, Schnermann J, Kurtz (2003) Preserved macula densa-dependent renin secretion in A1 adenosine receptor knockout mice. Am J Physiol 284:F770–F777

    CAS  Google Scholar 

  44. Traynor TR, Smart A, Briggs JP, Schnermann J (1999) Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. Am J Physiol 277:F706–F710

    CAS  PubMed  Google Scholar 

  45. Wagner C, Pfeifer A, Ruth P, Hofmann F, Kurtz A (1998) Role of cGMP-kinase II in the control of renin secretion and renin expression. J Clin Invest 102:1576–1582

    CAS  PubMed  Google Scholar 

  46. Wagner C, Godecke A, Ford M, Schnermann J, Schrader J, Kurtz A (2000) Regulation of renin gene expression in kidneys of eNOS- and nNOS-deficient mice. Pflugers Arch 439:567–572

    CAS  PubMed  Google Scholar 

  47. Wang JL, Cheng HF, Harris RC (1999) Cyclooxygenase-2 inhibition decreases renin content and lowers blood pressure in a model of renovascular hypertension. Hypertension 34:96–101

    CAS  PubMed  Google Scholar 

  48. Wolf K, Castrop H, Hartner A, Goppelt-Strube M, Hilgers KF, Kurtz A (1999) Inhibition of the renin-angiotensin system upregulates cyclooxygenase-2 expression in the macula densa. Hypertension 34:503–507

    CAS  PubMed  Google Scholar 

  49. Yang T, Huang YG, Singh I, Schnermann J, Briggs JP (1996) Localization of bumetanide- and thiazide-sensitive Na-K-Cl cotransporters along the rat nephron. Am J Physiol 271:F931–F939

    CAS  PubMed  Google Scholar 

  50. Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, Briggs JP (1998) Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol 274:F481–F489

    CAS  PubMed  Google Scholar 

  51. Yang T, Endo Y, Huang YG, Smart A, Briggs JP, Schnermann J (2000) Renin expression in Cox-2-knockout mice on normal or low-salt diets. Am J Physiol 279:F819–F825

    CAS  Google Scholar 

  52. Yang T, Huang YG, Schnermann JB, Briggs JP (2002) Hypertension and renal failure in Cox-2 knockout mice are affected by genetic background and gender. J Am Soc Nephrol 13:29A

    Google Scholar 

  53. Yang T, Paliege A, Mizel D, Huang G, Briggs JP, Schnermann JB (2002) Interaction between Cox-2 and Nos I in macula densa: negative feedback in control of renin release. J Am Soc Nephrol 13:A

    Google Scholar 

  54. Yuan CJ, Mandal AK, Zhang Z, Mukherjee AB (2000) Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. Cancer Res 60:1084–1091

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The skillful assistance provided by Marie-Luise Schweiger is gratefully acknowledged. The work was financially supported by grants from the Deutsche Forschungsgemeinschaft (Ku859/12-2).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charlotte Wagner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, C., Vitzthum, H., Castrop, H. et al. Differential regulation of renin and Cox-2 expression in the renal cortex of C57Bl/6 mice. Pflugers Arch - Eur J Physiol 447, 214–222 (2003). https://doi.org/10.1007/s00424-003-1157-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-003-1157-1

Keywords

Navigation