Skip to main content

Advertisement

SpringerLink
Log in

Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides

  • Original Article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Background and aim

The infusion of chronic angiotensin II (Ang II) has been shown to promote renal interstitial fibrosis. To evaluate the pathophysiological significance of the natriuretic peptide-GC-A system, we infused Ang II (1.0 mg/kg/day) in GC-A-deficient mice (GC-A-KO).

Methods

We used 5 groups (Wild-Saline n = 12, Wild-Ang II n = 14, GC-A-KO-Saline n = 11, GC-A-KO-Ang II n = 13, and GC-A-KO-Ang II-Hydralazine n = 10). Saline or Ang II was infused subcutaneously using an osmotic minipump for 3 weeks. Hydralazine was administered orally (0.05 g/L in drinking water).

Results

Systolic blood pressure was significantly higher in the GC-A-KO-Saline group (130 ± 12 mmHg) than in the Wild-Saline group (105 ± 30 mmHg), and was similar to that in the Wild-Ang II (141 ± 17 mmHg) and GC-A-KO-Ang II-Hydralazine (140 ± 20 mmHg) groups. Systolic blood pressure was significantly higher in the GC-A-KO-Ang II group (159 ± 21 mmHg) than in the 4 other groups. Renal tubular atrophy and interstitial fibrosis were significantly more severe in the GC-A-KO-Ang II group (atrophy 13.4 %, fibrosis 12.0 %) than in the Wild-Saline (0, 2.0 %), Wild-Ang II (2.9, 4.4 %), and GC-A-KO-Saline (0, 2.6 %) groups. Hydralazine could not inhibit this aggravation (GC-A-KO-Ang II-Hydralazine 13.5, 11.3 %). The expression of monocyte chemotactic protein-1 in tubular cells, and F4/80 and alpha-smooth muscle actin in the interstitium was clearly detected in the Ang II-infused wild and GC-A-KO groups and was associated with renal tubular atrophy and interstitial fibrosis. The expression of E-cadherin in tubular cells was absent in the Ang II-infused wild and GC-A-KO groups and was associated with renal tubular atrophy.

Conclusions

The natriuretic peptide-GC-A system may play an inhibitory role in Ang II-induced renal tubular atrophy, interstitial fibrosis, and phenotypic transformation in renal tubular cells and fibroblasts.

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

Similar content being viewed by others

References

  1. Kasahara M, Mukoyama M, Sugawara A, et al. Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol. 2000;11:1691–701.

    CAS  PubMed  Google Scholar 

  2. Suganami T, Mukoyama M, Sugawara A, et al. Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury. J Am Soc Nephrol. 2001;12:2652–63.

    CAS  PubMed  Google Scholar 

  3. Makino H, Mukoyama M, Mori K, et al. Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice. Diabetologia. 2006;49:2514–24.

    Article  CAS  PubMed  Google Scholar 

  4. Saito Y. Roles of atrial natriuretic peptide and its therapeutic use. J Cardiol. 2010;56:262–70.

    Article  PubMed  Google Scholar 

  5. Lopez MJ, Wong SK, Kishimoto I, et al. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature. 1995;378:65–8.

    Article  CAS  PubMed  Google Scholar 

  6. Sabrane K, Kruse MN, Fabritz L, et al. Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide. J Clin Invest. 2005;115:1666–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Chen W, Gassner B, Börner S, et al. Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway. Cardiovasc Res. 2012;93:141–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Ogawa Y, Mukoyama M, Yokoi H, et al. Natriuretic peptide receptor guanylyl cyclase-a protects podocytes from aldosterone-induced glomerular injury. J Am Soc Nephrol. 2012;23:1198–209.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Blasi ER, Rocha R, Rudolph AE, Blomme EA, Polly ML, McMahon EG. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003;63:1791–800.

    Article  CAS  PubMed  Google Scholar 

  10. Faulkner JL, Szcykalski LM, Springer F, Barnes JL. Origin of interstitial fibroblasts in an accelerated model of angiotensin II-induced renal fibrosis. Am J Pathol. 2005;167:1193–205.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Mitani H, Ishizaka N, Aizawa T, et al. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension. 2002;39:838–43.

    Article  CAS  PubMed  Google Scholar 

  12. Johnson RJ, Alpers CE, Yoshimura A, et al. Renal injury from angiotensin II-mediated hypertension. Hypertension. 1992;19:464–74.

    Article  CAS  PubMed  Google Scholar 

  13. Lombardi DM, Viswanathan M, Vio CP, Saavedra JM, Schwartz SM, Johnson RJ. Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent. Nephron. 2001;87:66–74.

    Article  CAS  PubMed  Google Scholar 

  14. Kitayama H, Maeshima Y, Takazawa Y, et al. Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries. Am J Hypertens. 2006;19:718–27.

    Article  CAS  PubMed  Google Scholar 

  15. Ozawa Y, Kobori H, Suzaki Y, Navar LG. Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions. Am J Physiol Renal Physiol. 2007;292:F330–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Giachelli CM, Pichler R, Lombardi D, et al. Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. Kidney Int. 1994;45:515–24.

    Article  CAS  PubMed  Google Scholar 

  17. Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 1995;20:1–17.

    Article  Google Scholar 

  18. Desmoulière A, Darby IA, Gabbiani G. Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosis. Lab Invest. 2003;83:1689–707.

    Article  PubMed  Google Scholar 

  19. Tokudome T, Horio T, Kishimoto I, et al. Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides. Circulation. 2005;111:3095–104.

    Article  CAS  PubMed  Google Scholar 

  20. Quesada A, Vargas F, Montoro-Molina S, et al. Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. PLoS ONE. 2012;7:e40402.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Li P, Oparil S, Novak L, et al. ANP signaling inhibits TGF-beta-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells. J Appl Physiol. 2007;102:390–8.

    Article  CAS  PubMed  Google Scholar 

  22. Weber NC, Blumenthal SB, Hartung T, Vollmar AM, Kiemer AK. ANP inhibits TNF-alpha-induced endothelial MCP-1 expression–involvement of p38 MAPK and MKP-1. J Leukoc Biol. 2003;74:932–41.

    Article  CAS  PubMed  Google Scholar 

  23. Suzuki K, Han GD, Miyauchi N, et al. Angiotensin II type 1 and type 2 receptors play opposite roles in regulating the barrier function of kidney glomerular capillary wall. Am J Pathol. 2007;170:1841–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Baltatu O, Silva JA Jr, Ganten D, Bader M. The brain renin-angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy. Hypertension. 2000;35(part 2):409–12.

    Article  CAS  PubMed  Google Scholar 

  25. Cargill RI, Coutie WJ, Lipworth BJ. The effects of angiotensin II on circulating levels of natriuretic peptides. Br J Clin Pharmacol. 1994;38:139–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Marin-Grez M, Fleming JT, Steinhausen M. Atrial natriuretic peptide causes pre-glomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature. 1986;324:473–6.

    Article  CAS  PubMed  Google Scholar 

  27. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17:2974–84.

    Article  CAS  PubMed  Google Scholar 

  28. Manotham K, Tanaka T, Matsumoto M, et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int. 2004;65:871–80.

    Article  PubMed  Google Scholar 

  29. Sun S, Ning X, Zhang Y, et al. Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int. 2009;75:1278–87.

    Article  CAS  PubMed  Google Scholar 

  30. Long DA, Mu W, Price KL, et al. Vascular endothelial growth factor administration does not improve microvascular disease in the salt-dependent phase of post-angiotensin II hypertension. Am J Physiol Renal Physiol. 2006;291:F1248–54.

    Article  CAS  PubMed  Google Scholar 

  31. Parekh N, Zou AP. Role of prostaglandins in renal medullary circulation: response to different vasoconstrictors. Am J Physiol. 1996;271:F653–8.

    CAS  PubMed  Google Scholar 

  32. Zhu Q, Wang Z, Xia M, et al. Silencing of hypoxia-inducible factor-1α gene attenuated angiotensin II-induced renal injury in Sprague-Dawley rats. Hypertension. 2011;58:657–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Tokudome T, Kishimoto I, Yamahara K, et al. Impaired recovery of blood flow after hind-limb ischemia in mice lacking guanylyl cyclase-A, a receptor for atrial and brain natriuretic peptides. Arterioscler Thromb Vasc Biol. 2009;29:1516–21.

    Article  CAS  PubMed  Google Scholar 

  34. Sexton PM, Zhuo J, Mendelsohn FA. Localization and regulation of renal receptors for angiotensin II and atrial natriuretic peptide. Tohoku J Exp Med. 1992;166:41–56.

    Article  CAS  PubMed  Google Scholar 

  35. Garg R, Pandey KN. Angiotensin II-mediated negative regulation of Npr1 promoter activity and gene transcription. Hypertension. 2003;41(part 2):730–6.

    Article  CAS  PubMed  Google Scholar 

  36. Arise KK, Pandey KN. Inhibition and down-regulation of gene transcription and guanylyl cyclase activity of NPRA by angiotensin II involving protein kinase C. Biochem Biophys Res Commun. 2006;349:131–5.

    Article  CAS  PubMed  Google Scholar 

  37. Hu P, Wang J, Zhao XQ, Hu B, Lu L, Qin YH. Overexpressed C-type natriuretic peptide serves as an early compensatory response to counteract extracellular matrix remodeling in unilateral ureteral obstruction rats. Mol Biol Rep. 2013;40:1429–41.

    Article  CAS  PubMed  Google Scholar 

  38. Segawa K, Minami K, Jimi N, Nakashima Y, Shigematsu A. C-type natriuretic peptide inhibits rat mesangial cell proliferation by a phosphorylation-dependent mechanism. Naunyn Schmiedebergs Arch Pharmacol. 1998;357:70–6.

    Article  CAS  PubMed  Google Scholar 

  39. Canaan-Kühl S, Ostendorf T, Zander K, Koch KM, Floege J. C-type natriuretic peptide inhibits mesangial cell proliferation and matrix accumulation in vivo. Kidney Int. 1998;53:1143–51.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Howard Hughes Medical Institute for the GC-A knockout mice, Dr. Kyoko Shioya for her support, and Tamaki Mabuchi and Junko Nakamura for their excellent technical assistance. This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan (No. 22590906).

Conflict of interest

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan

    Fumiki Yoshihara, Takeshi Horio & Yuhei Kawano

  2. Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Suita, Osaka, Japan

    Takeshi Tokudome & Kenji Kangawa

  3. Division of Atherosclerosis and Diabetes, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan

    Ichiro Kishimoto

  4. Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Research Institute, Suita, Osaka, Japan

    Kentaro Otani

  5. Division of Nephrology and Hypertension, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan

    Atsunori Kuwabara

Authors
  1. Fumiki Yoshihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Tokudome
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ichiro Kishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kentaro Otani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Atsunori Kuwabara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Horio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuhei Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenji Kangawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fumiki Yoshihara.

Electronic supplementary material

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yoshihara, F., Tokudome, T., Kishimoto, I. et al. Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides. Clin Exp Nephrol 19, 197–207 (2015). https://doi.org/10.1007/s10157-014-0982-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-014-0982-1

Keywords

Search

Navigation