Skip to main content

Advertisement

SpringerLink
Log in

Involvement of the renin–angiotensin system in the development of nephrogenic systemic fibrosis-like lesions in the RenTag mouse model

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

Abstract

Background

Renin–angiotensin system (RAS) activation increases angiotensin II production stimulating profibrotic factors, especially in the setting of chronic kidney disease. Nephrogenic systemic fibrosis (NSF) has been associated with gadolinium (Gd) exposure and renal failure. RAS involvement in NSF is unclear compared to transforming growth factor beta and Smad. RenTag mice were chosen to investigate the role of RAS in NSF-like dermal fibrosis because they demonstrated dermal fibrosis at birth, perturbations of RAS in subcutaneous tissue, and renal failure within 4 weeks of age.

Methods

Wild-type and RenTag mice were injected weekly with a supratherapeutic dose of intravenous gadodiamide (3.0 mmol/kg body weight) and killed at 12 weeks of age for skin and kidney histology.

Results

RenTag mice had elevated BUN levels, pitted kidneys, and glomerular damage. RenTag mice skin revealed an increased density of fibroblasts, no mucopolysaccharide deposits, and increased collagen fibril density regardless of Gd exposure. Skin and kidney histopathology of wild-type mice were normal regardless of Gd exposure. CD34 positivity was higher in RenTag compared to wild-type.

Conclusions

Since RenTag dermal lesions remained unchanged after gadolinium exposure in the setting of renal failure, this animal model suggests perturbations of subcutaneous RAS may be involved in Gd-naïve dermal fibrosis.

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

Similar content being viewed by others

References

  1. Aros C, Remuzzi G. The Renin–angiotensin system in progression, remission and regression of chronic nephropathies. J Hypertens Suppl. 2002;20:45–53.

    Article  Google Scholar 

  2. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of Renin–angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int. 2005;68:57–65.

    Article  Google Scholar 

  3. Kanno Y, Takenaka T, Nakamura T, Suzuki H. Add-on angiotensin receptor blocker in patients who have proteinuric chronic kidney diseases and are treated with angiotensin-converting enzyme inhibitors. Clin J Am Soc Nephrol. 2006;1:730–7.

    Article  CAS  PubMed  Google Scholar 

  4. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Inter Med. 2008;148:30–48.

    Article  Google Scholar 

  5. Lewis E, Hunsicker L, Clarke W, Pohl M, Lewis J, Ritz E, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.

    Article  CAS  PubMed  Google Scholar 

  6. Li P, Leung C, Chow K, Cheng Y, Fung S, Mak S, Tang A, Yung J, Yu A, Szeto C. Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study. Am J Kidney Dis. 2006;47:751–60.

    Article  CAS  PubMed  Google Scholar 

  7. Ruiz-Ortega M, Egido J. Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts. Kidney Int. 1997;52:1497–510.

    Article  CAS  PubMed  Google Scholar 

  8. Kagami S, Border W, Miller D, Noble N. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest. 1994;93:2431–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Iwano M, Plieth D, Danoff T, Xue C, Okada H, Neilson E. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002;110:341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sanchez-Lopez E, Rodrigues D, Rodriguez V, Reyego M, Rodriguez G, Lavoz B, Mezzano S, Egido J, Ortiz A, Ruiz-Ortega M. Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage. Nefrologia. 2009;29:382–91.

    CAS  PubMed  Google Scholar 

  11. Schneider A, Panzer U, Zahner G, Wenzel U, Wolf G, Thaiss F, Helmchen U, Stahl R. Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-beta. Kidney Int. 1999;56:135–44.

    Article  CAS  PubMed  Google Scholar 

  12. Wolf G, Haberstroh U, Neilson E. Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol. 1992;140:95–107.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wolf G, Zahner G, Schroeder R, Stahl R. Transforming growth factor beta mediates the angiotensin-II-induced stimulation of collagen type IV synthesis in cultured murine proximal tubular cells. Nephrol Dial Transplant. 1996;11:263–9.

    Article  CAS  PubMed  Google Scholar 

  14. Wolf G. Angiotensin II as a mediator of tubulointerstitial injury. Nephrol Dial Transplant. 2000;15:61–3.

    Article  CAS  PubMed  Google Scholar 

  15. Cowper S, Rabach M, Girardi M. Clinical and histological findings in nephrogenic systemic fibrosis. Euro J Radiol. 2008;66:191–9.

    Article  Google Scholar 

  16. Galan A, Cowper S, Bucala R. Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol. 2006;18:614–7.

    Article  PubMed  Google Scholar 

  17. Cowper S, Bucala R, Leboit P. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight. Semin Arthritis Rheum. 2006;35:208–10.

    Article  PubMed  Google Scholar 

  18. Jimenez S, Artlett C, Sandorfi N, Derk C, Latinis K, Haddad R, Shanahan J. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum. 2004;50:2660–6.

    Article  CAS  PubMed  Google Scholar 

  19. Mendoza F, Artlett C, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum. 2006;35:238–49.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jacob HJ, Sigmund CD, Shockley TR, Gross KW, Dzau VJ. Renin promoter SV40 T-antigen transgenic mouse. A model of primary renal vascular hyperplasia. Hypertension. 1991;17(6 Pt 2):1167–62.

    Article  CAS  PubMed  Google Scholar 

  21. Sigmund C, Okuyama K, Ingelfinge, Jones C, Mullins J, Kane C, Kim U, Wu C, Kenny L, Rustum Y. Isolation and characterization of renin-expressing cell lines from transgenic mice containing a renin-promotor viral oncogene fusion construct. J Biochem. 1990;265:19916–22.

    CAS  Google Scholar 

  22. Cowper S, Bucala R. Nephrogenic fibrosing dermopathy: suspect identified, motive unclear. Am J Dermatopathol. 2003;4:358.

    Article  Google Scholar 

  23. Kucher C, Xu X, Pasha T, Elenitsas R. Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol. 2005;32:484–90.

    Article  PubMed  Google Scholar 

  24. Gagnon R, Duguid W. A reproducible model for chronic renal failure in the mouse. Urol Res. 1983;11:11–4.

    Article  CAS  PubMed  Google Scholar 

  25. Sigmund C, Jones C, Fabian J, Mullins J, Gross K. Tissue and cell specific expression of a renin promoter-reporter gene construct in transgenic mice. Biochem Biophys Res Commun. 1990;170:344–50.

    Article  CAS  PubMed  Google Scholar 

  26. Sigmund C, Jones C, Jacob H, Ingelfinger J, Kim U, Gamble D, Dzau V, Gross K. Pathophysiology of vascular smooth muscle in renin-promotor-T-antigen transgenic mice. Am J Physiol Renal Physiol. 1991;260:F249–57.

    CAS  Google Scholar 

  27. Stawski L, Han R, Bujor A, Trojanowska M. Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis. Arthritis Res Ther. 2012;14:R194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ito Y, Aten J, Bende R, Oemar B, Rabelink T, Weening J, Goldschmeding R. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int. 1998;53:853–61.

    Article  CAS  PubMed  Google Scholar 

  29. Mezzano S, Ruiz-Orega M, Egido J. Angiotensin II and renal fibrosis. Hypertension. 2001;38:635–8.

    Article  CAS  PubMed  Google Scholar 

  30. Ruiz-Ortega M, Lorenzo O, Suzuki Y, Ruperez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol and Hypertens. 2001;10:321–9.

    Article  CAS  Google Scholar 

  31. Sigmund C, Jones C, Mullins J, Kim U, Gross K. Expression of murine renin genes in subcutaneous connective tissue. Proc Natl Acad Sci. 1990;87:7993–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Langer R, Lorke D, Neidl van Gorkom K, Petroianu G, Azimullah S, Singh S, Fuchsjager M. In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents. European J Radiol. 2012;81:2562–7.

    Article  CAS  Google Scholar 

  33. Grant D, Johnson H, Juelsrud A, Lovhaug D. Effects of gadolinium contrast agents in naïve and nephrectomized rats: relevance to nephrogenic systemic fibrosis. Acta Radiol. 2009;50:156–69.

    Article  CAS  PubMed  Google Scholar 

  34. Wahba I, Simpson E, White K. Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. Am J Transplant. 2007;7:2425–32.

    Article  CAS  PubMed  Google Scholar 

  35. Kelly B, Petitt M, Sanchez R. Nephrogenic systemic fibrosis is associated with transforming growth factor beta and Smad without evidence of Renin–angiotensin system involvement. J Am Acad Dermatol. 2008;58:1025–30.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Mary Kay Ellsworth for animal husbandry, Michael Rusiniak for assistance with photography, and HL048459 (KWG) and Roswell Park Cancer Institute core grant CA016056 for support.

Conflict of interest

The authors state no conflict of interest. This project was funded with a grant from the National Kidney Foundation of WNY. Dr. Mandip Panesar has served as an expert witness on NSF cases. Dr. George Hajduczok is also a practicing attorney. He is not involved in litigation related to the subject matter of this study.

Author information

Authors and Affiliations

  1. Erie County Medical Center, State University of New York at Buffalo, 462 Grider Street, Buffalo, NY, 14215, USA

    Ryan Tulowitzki, Silvi Shah, George Hajduczok & Mandip Panesar

  2. Roswell Park Cancer Institute, Buffalo, NY, USA

    Sandra Sexton, Craig A. Jones & Kenneth W. Gross

Authors
  1. Sandra Sexton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryan Tulowitzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig A. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvi Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George Hajduczok
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenneth W. Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mandip Panesar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mandip Panesar.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sexton, S., Tulowitzki, R., Jones, C.A. et al. Involvement of the renin–angiotensin system in the development of nephrogenic systemic fibrosis-like lesions in the RenTag mouse model. Clin Exp Nephrol 20, 162–168 (2016). https://doi.org/10.1007/s10157-015-1141-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-015-1141-z

Keywords

Search

Navigation