Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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

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 to check access.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

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

References

  1. 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

  2. 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

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

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

  5. 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

  6. 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

  7. 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

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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

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

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

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

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

  21. 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

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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

Download references

Author information

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

  • Kidney
  • Nitric oxide synthase
  • Angiotensin II
  • Hypotension
  • Dietary salt loading
  • Perfusion pressure
  • Mouse (ICR, Atg+/+; Atg−/−)