Skip to main content

Advertisement

SpringerLink
Log in

Expression of endothelial nitric oxide synthase is suppressed in the renal vasculature of angiotensinogen-gene knockout mice

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

We have attempted to elucidate the mechanism by which endothelial-type nitric oxide synthase (eNOS) is regulated in the kidney, with special reference to the role of renal hemodynamics and angiotensin II (Ang II). We compared angiotensinogen gene knockout (Atg−/−) mice, which lacked Ang II (resulting in sodium/water depletion and severe hypotension), with wild-type (Atg+/+) mice. Using Western blot analysis and the NADPH diaphorase histochemical reaction, we found that the expression and activity of eNOS were markedly lower in the renal vessels of Atg−/− mice compared with wild-type (Atg+/+) mice. Dietary salt loading significantly enhanced renal eNOS levels and increased blood pressure in Atg−/− mice, but severe hypotension almost abolished the effects of salt loading. In contrast, in Atg+/+ mice, altered salt intake or hydralazine had no effect on renal eNOS levels. These results suggest that perfusion pressure plays an essential role in maintaining renal vascular eNOS activity, whereas Ang II plays a supportive role, especially when renal circulation is impaired.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Barton CH, Ni Z, Vaziri ND (2001) Effect of severe aortic banding above the renal arteries on nitric oxide synthase isotype expression. Kidney Int 59:654–661

    Article  PubMed  CAS  Google Scholar 

  • Baylis C, Harton P, Engels K (1990) Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol 1:875–881

    PubMed  CAS  Google Scholar 

  • Bayraktutan U (2003) Effects of angiotensin II on nitric oxide generation in growing and resting rat aortic endothelial cells. J Hypertens 21:2093–2101

    Article  PubMed  CAS  Google Scholar 

  • Braam B (1999) Renal endothelial and macula densa NOS integrated response to changes in extracellular fluid volume. Am J Physiol 276:R1551–R1561

    PubMed  CAS  Google Scholar 

  • Brede M, Roell W, Ritter O, Wiesmann F, Jahns R, Haase A, Fleischmann BK, Hein L (2003) Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension 42:1177–1182

    Article  PubMed  CAS  Google Scholar 

  • Chin SY, Wang CT, Majid DS, Navar LG (1998) Renoprotective effects of nitric oxide in angiotensin II-induced hypertension in the rat. Am J Physiol 274:F876–F882

    PubMed  CAS  Google Scholar 

  • Gragasin FS, Xu Y, Arenas IA, Kainth N, Davidge ST (2003) Estrogen reduces angiotensin II-induced nitric oxide synthase and NAD(P)H oxidase expression in endothelial cells. Arterioscler Thromb Vasc Biol 23:38–44

    Article  PubMed  CAS  Google Scholar 

  • Hennington BS, Zhang H, Miller MT, Granger JP, Reckelhoff JF (1998) Angiotensin II stimulates synthesis of endothelial nitric oxide synthase. Hypertension 31:283–288

    PubMed  CAS  Google Scholar 

  • Hill-Kapturczak N, Kapturczak MH, Block ER, Patel JM, Malinski T, Madsen KM, Tisher CC (1999) Angiotensin II-stimulated nitric oxide release from porcine pulmonary endothelium is mediated by angiotensin IV. J Am Soc Nephrol 10:481–491

    PubMed  CAS  Google Scholar 

  • Ito S, Johnson CS, Carretero OA (1991) Modulation of angiotensin II-induced vasoconstriction by endothelium-derived relaxing factor in the isolated microperfused rabbit afferent arteriole. J Clin Invest 87:1656–1663

    Article  PubMed  CAS  Google Scholar 

  • Just A, Ehmke H, Wittmann U, Kirchheim HR (2002) Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog. J Physiol (Lond) 538:167–177

    Article  CAS  Google Scholar 

  • Kammerl MC, Grimm D, Kromer EP, Jabusch HC, Reif R, Morhard S, Endemann D, Fischereder M, Riegger GA, Kramer BK (2002) Effects of aortic stenosis on renal renin, angiotensin receptor, endothelin and NOS gene expression in rats. Am J Nephrol 22:84-89

    Article  PubMed  Google Scholar 

  • Kihara M, Umemura S, Kadota T, Yabana M, Tamura K, Nyuui N, Ogawa N, Murakami K, Fukamizu A, Ishii M (1997) The neuronal isoform of constitutive nitric oxide synthase is up-regulated in the macula densa of angiotensinogen gene-knockout mice. Lab Invest 76:285–294

    PubMed  CAS  Google Scholar 

  • Kihara M, Umemura S, Yabana M, Sumida Y, Nyui N, Tamura K, Kadota T, Kishida R, Murakami K, Fukamizu A, Ishii M (1998a) Dietary salt loading decreases the expressions of neuronal-type nitric oxide synthase and renin in the juxtaglomerular apparatus of angiotensinogen gene-knockout mice. J Am Soc Nephrol 9:355–362

    PubMed  CAS  Google Scholar 

  • Kihara M, Umemura S, Sumida Y, Yokoyama N, Yabana M, Nyui N, Tamura K, Murakami K, Fukamizu A, Ishii M (1998b) Genetic deficiency of angiotensinogen produces an impaired urine concentrating ability in mice. Kidney Int 53:548–555

    Article  PubMed  CAS  Google Scholar 

  • Kihara M, Umemura S, Sugaya T, Toya Y, Yabana M, Kobayashi S, Tamura K, Kadota T, Kishida R, Murakami K, Fukamizu A, Ishii M (1998c) 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

    Article  PubMed  CAS  Google Scholar 

  • Majid DSA, Navar LG (1992) Suppression of blood flow autoregulation plateau during nitric oxide blockade in canine kidney. Am J Physiol 262:F40–F46

    PubMed  CAS  Google Scholar 

  • Majid DSA, Navar G (2001) Nitric oxide in the control of renal hemodynamics and excretory function. Am J Hypertens 14:74S–82S

    Article  PubMed  CAS  Google Scholar 

  • Majid DSA, Omoro SA, Chin SY, Navar LG (1998) Intrarenal nitric oxide activity and pressure natriuresis in anesthetized dogs. Hypertension 32:266–272

    PubMed  CAS  Google Scholar 

  • Mattson DL, Higgins DJ (1996) Influence of dietary sodium intake on renal medullary nitric oxide synthase. Hypertension 27:688–692

    PubMed  CAS  Google Scholar 

  • Moreno C, Lopez A, Llinas MT, Rodriguez F, Lopez-Farre A, Nava E, Salazar FJ (2002) Changes in NOS activity and protein expression during acute and prolonged ANG II administration. Am J Physiol Regul Integr Comp Physiol 282:R31–R37

    PubMed  CAS  Google Scholar 

  • Navar LG (1998) Integrating multiple paracrine regulators of renal microvascular dynamics. Am J Physiol 274:F433–F444

    PubMed  CAS  Google Scholar 

  • Nishimoto Y, Tomida T, Matsui H, Ito T, Okumura K (2002) Decrease in renal medullary endothelial nitric oxide synthase of fructose-fed, salt-sensitive hypertensive rats. Hypertension 40:190–194

    Article  PubMed  CAS  Google Scholar 

  • Okubo S, Niimura M, Matsusaka T, Fogo A, Hogan BL, Ichikawa I (1998) Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption. Kidney Int 53:617–625

    Article  PubMed  CAS  Google Scholar 

  • Olson SC, Dowds TA, Pino PA, Barry MT, Burke-Wolin T (1997) Ang II stimulates endothelial nitric oxide synthase expression in bovine pulmonary artery endothelium. Am J Physiol 273:L315–L321

    PubMed  CAS  Google Scholar 

  • Olson SC, Oeckler R, Li X, Du L, Traganos F, Zhao X, Burke-Wolin T (2004) Angiotensin II stimulates nitric oxide production in pulmonary artery endothelium via the type 2 receptor. Am J Physiol Lung Cell Mol Physiol 287:L559–L568

    Article  PubMed  CAS  Google Scholar 

  • Pueyo ME, Arnal JF, Rami J, Michel JB (1998) Angiotensin II stimulates the production of NO and peroxynitrite in endothelial cells. Am J Physiol 274:C214–C220

    PubMed  CAS  Google Scholar 

  • Sato K, Kihara M, Hashimoto T, Matsushita K, Koide Y, Tamura K, Hirawa N, Toya Y, Fukamizu A, Umemura S (2004) Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1a receptor gene knockout mice. J Am Soc Nephrol 15:1756–1763

    Article  PubMed  CAS  Google Scholar 

  • Schnermann J (1998) Juxtaglomerular cell complex in the regulation of renal salt excretion. Am J Physiol 274:R263–R279

    PubMed  CAS  Google Scholar 

  • Schricker K, Potzl B, Hamann M, Kurtz A (1996) Coordinate changes of renin and brain-type nitric-oxide-synthase (b-NOS) mRNA levels in rat kidneys. Pflugers Arch 432:394–400

    Article  PubMed  CAS  Google Scholar 

  • Singh I, Grams M, Wang WH, Yang T, Killen P, Smart A, Schnermann J, Briggs JP (1996) Coordinate regulation of renal expression of nitric oxide synthase, renin, and angiotensinogen mRNA by dietary salt. Am J Physiol 270:F1027–F1037

    PubMed  CAS  Google Scholar 

  • Sorensen CM, Leyssac PP, Skott O, Holstein-Rathlou NH (2000) Role of the renin-angiotensin system in regulation and autoregulation of renal blood flow. Am J Physiol Regul Intergr Comp Physiol 279:R1017–R1024

    CAS  Google Scholar 

  • Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K, Fukamizu A, Murakami K (1994) Angiotensinogen-deficient mice with hypotension. J Biol Chem 269:31334–31337

    PubMed  CAS  Google Scholar 

  • Umemura S, Kihara M, Sumida Y, Yabana M, Ishigami T, Tamura K, Nyui N, Hibi K, Murakami K, Fukamizu A, Ishii M (1998) Endocrinological abnormalities in angiotensinogen-gene knockout mice:studies of hormonal responses to dietary salt loading. J Hypertens 16:285–289

    Article  PubMed  CAS  Google Scholar 

  • Vaziri ND, Ni Z, Zhang YP, Ruzics EP, Maleki P, Ding Y (1998) Depressed renal and vascular nitric oxide synthase expression in cyclosporine-induced hypertension. Kidney Int 54:482–491

    Article  PubMed  CAS  Google Scholar 

  • Vaziri ND, Ni Z, Oveisi F, Trnavsky-Hobbs DL (2000) Effect of antioxidant therapy on blood pressure and NO synthase expression in hypertensive rats. Hypertension 36:957–964

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine II, School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, 236-0004, Japan

    Minoru Kihara, Keiko Sato, Tatsuo Hashimoto, Nozomi Imai, Yoshiyuki Toya & Satoshi Umemura

Authors
  1. Minoru Kihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiko Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuo Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nozomi Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiyuki Toya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Umemura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minoru Kihara.

Additional information

This study was supported by Grants-in-Aid for Scientific Resarch 2001–2003, Japan Society for Promotion of Science (grant no. 13670735).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kihara, M., Sato, K., Hashimoto, T. et al. Expression of endothelial nitric oxide synthase is suppressed in the renal vasculature of angiotensinogen-gene knockout mice. Cell Tissue Res 323, 313–320 (2006). https://doi.org/10.1007/s00441-005-0058-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-005-0058-3

Search

Navigation