Advertisement

Molecular Medicine

, Volume 17, Issue 11–12, pp 1204–1212 | Cite as

Protective Effect of TRPV1 against Renal Fibrosis via Inhibition of TGF-β/Smad Signaling in DOCA-Salt Hypertension

  • Youping Wang
  • Donna H. Wang
Research Article

Abstract

To investigate the effects of the transient receptor potential vanilloid type 1 (TRPV1) channel on renal extracellular matrix (ECM) protein expression including collagen deposition and the transforming growth factor β (TGF-β)/Smad signaling pathway during salt-dependent hypertension, wild-type (WT) and TRPV1-null (TRPV1−/−) mutant mice were uninephrectomized and given deoxycorticosterone acetate (DOCA)-salt for 4 wks. TRPV1 gene ablation exaggerated DOCA-salt-induced impairment of renal function as evidenced by increased albumin excretion (µg/24 h) compared with WT mice (83.7 ± 7.1 versus 28.3 ± 4.8, P < 0.05), but had no apparent effect on mean arterial pressure (mmHg) as determined by radiotelemetry (141 ± 4 versus 138 ± 3, P > 0.05). Morphological analysis showed that DOCA-salt-induced glomerulosclerosis, tubular injury and macrophage infiltration (cells/mm2) were increased in TRPV1−/− compared with WT mice (0.74 ± 0.08 versus 0.34 ± 0.04; 3.14 ± 0.26 versus 2.00 ± 0.31; 68 ± 5 versus 40 ± 4, P < 0.05). Immunostaining studies showed that DOCA-salt treatment decreased nephrin but increased collagen type I and IV as well as phosphorylated Smad2/3 staining in kidneys of TRPV1−/− compared with WT mice. Hydroxyproline assay and Western blot showed that DOCA-salt treatment increased collagen content (µg/mg dry tissue) and fibronectin protein expression (%β-actin arbitrary units) in the kidney of TRPV1−/− compared with WT mice (26.7 ± 2.7 versus 17.4 ± 1.8; 0.93 ± 0.07 versus 0.65 ± 0.08, P < 0.05). Acceleration of renal ECM protein deposition in DOCA-salt-treated TRPV1−/− mice was accompanied by increased TGF-β1, as well as phosphorylation of Smad2/3 protein expression (%β-actin arbitrary units) compared with DOCA-salt-treated WT mice (0.61 ± 0.07 versus 0.32 ± 0.05; 0.57 ± 0.07 versus 0.25 ± 0.05; 0.71 ± 0.08 versus 0.40 ± 0.06, P < 0.05). These results show that exaggerated renal functional and structural injuries are accompanied by increased production of ECM protein and activation of the TGF-β/Smad2/3 signaling pathway. These data suggest that activation of TRPV1 attenuates the progression of renal fibrosis possibly via suppression of the TGF-β and its downstream regulatory signaling pathway.

Notes

Acknowledgments

This work was supported in part by National Institutes of Health grants HL-57853, HL-73287 and DK67620 and a grant from the Michigan Economic Development Corporation. The authors thank Beihua Zhong for her excellent technical assistance.

References

  1. 1.
    Atkins RC. (2005) The epidemiology of chronic kidney disease. Kidney Int. 94:S14–18.CrossRefGoogle Scholar
  2. 2.
    Hartner A, Veelken R, Wittmann M, Cordasic N, Hilgers KF. (2005) Effects of diabetes and hypertension on macrophage infiltration and matrix expansion in the rat kidney. BMC Nephrol. 6:6.CrossRefGoogle Scholar
  3. 3.
    Eddy AA. (2000) Molecular basis of renal fibrosis. Pediatr. Nephrol. 15:290–301.CrossRefGoogle Scholar
  4. 4.
    Mason RM, Wahab NA. (2003) Extracellular matrix metabolism in diabetic nephropathy. J. Am. Soc. Nephrol. 14:1358–73.CrossRefGoogle Scholar
  5. 5.
    Wang W, Koka V, Lan HY. (2005) Transforming growth factor-β and Smad signaling in kidney disease. Nephrology. (Carlton) 10:48–56.CrossRefGoogle Scholar
  6. 6.
    Chabrier PE. (1996) Growth factors and vascular wall. Int. Angiol. 15:100–3.PubMedGoogle Scholar
  7. 7.
    Kretzschmar M, Massague J. (1998) SMADs: mediators and regulators of TGF-beta signaling. Curr. Opin. Genet. Dev. 8:103–11.CrossRefGoogle Scholar
  8. 8.
    Spriewald BM, Ensminger SM, Billing JS, Morris PJ, Wood KJ. (2003) Increased expression of transforming growth factor-beta and eosinophil infiltration is associated with the development of transplant arteriosclerosis in long-term surviving cardiac allografts. Transplantation. 76:1105–11.CrossRefGoogle Scholar
  9. 9.
    Ryan ST, Koteliansky VE, Gotwals PJ, Lindner V (2003) Transforming growth factor-beta-dependent events in vascular remodeling following arterial injury. J. Vasc. Res. 40:37–46.CrossRefGoogle Scholar
  10. 10.
    Mata-Greenwood E, Meyrick B, Steinhorn RH, Fineman JR, Black SM. (2003) Alterations in TGF-beta1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension. Am. J. Physiol. 285:L209–21.Google Scholar
  11. 11.
    Porreca E, et al. (1997) Increased transforming growth factor-beta production and gene expression by peripheral blood monocytes of hypertensive patients. Hypertension. 30:134–9.CrossRefGoogle Scholar
  12. 12.
    Caterina MJ, et al. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 288:306–13.CrossRefGoogle Scholar
  13. 13.
    Szallasi A, Blumberg PM. (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev. 51:159–212.PubMedGoogle Scholar
  14. 14.
    Julius D, Basbaum AI. (2001) Molecular mechanisms of nociception. Nature. 413:203–10.CrossRefGoogle Scholar
  15. 15.
    Wang Y, Kaminski NE, Wang DH. (2005) VR1-mediated depressor effects during high-salt intake: role of anandamide. Hypertension. 46:986–91.CrossRefGoogle Scholar
  16. 16.
    Wang Y, Kaminski NE, Wang DH. (2007) Endocannabinoid regulates blood pressure via activation of the TRPV1 in Wistar rats fed a high-salt diet. J. Pharmacol. Exp. Ther. 321:763–9.CrossRefGoogle Scholar
  17. 17.
    Wang Y, Babánková D, Huang J, Swain GM, Wang DH. (2008) Deletion of transient receptor potential vanilloid type 1 receptors exaggerates renal damage in deoxycorticosterone acetate-salt hypertension. Hypertension. 52:264–70.CrossRefGoogle Scholar
  18. 18.
    Saito T, Sumithran E, Glasgow EF, Atkins RC. (1987) The enhancement of aminonucleoside nephrosis by the co-administration of protamine. Kidney Int. 32:691–9.CrossRefGoogle Scholar
  19. 19.
    Shih W, Hines WH, Neilson EG. (1988) Effects of cyclosporin A on the development of immunemediated interstitial nephritis. Kidney Int. 33:1113–8.CrossRefGoogle Scholar
  20. 20.
    Wang YP, et al. (2002) Lipopolysaccharide triggers late preconditioning against myocardial infarction via inducible nitric oxide synthase. Cardiovasc. Res. 56:33–42.CrossRefGoogle Scholar
  21. 21.
    Mundel P, Shankland SJ. (2002) Podocyte biology and response to injury. J. Am. Soc. Nephrol. 13:3005–15.CrossRefGoogle Scholar
  22. 22.
    Kerjaschki D. (2001) Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J. Clin. Invest. 108:1583–7.CrossRefGoogle Scholar
  23. 23.
    Ying WZ, Sanders PW. (2003) The interrelationship between TGF-beta1 and nitric oxide is altered in salt-sensitive hypertension. Am. J. Physiol. 285:F902–8.Google Scholar
  24. 24.
    Socha MJ, Manhiani M, Said N, Imig JD, Motamed K. (2007) Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension. Am. J. Pathol. 171:1104–12.CrossRefGoogle Scholar
  25. 25.
    Zhu S, Liu Y, Wang L, Meng QH. (2008) Transforming growth factor-beta1 is associated with kidney damage in patients with essential hypertension: renoprotective effect of ACE inhibitor and/or angiotensin II receptor blocker. Nephrol. Dial. Transplant. 23:2841–6.CrossRefGoogle Scholar
  26. 26.
    Ziyadeh FN, et al. (2000) Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc. Natl. Acad. Sci. U.S.A. 97:8015–20.CrossRefGoogle Scholar
  27. 27.
    Matsuda H, et al. (2006) Development of gene silencing pyrrole-imidazole polyamide targeting the TGF-beta1 promoter for treatment of progressive renal diseases. J. Am. Soc. Nephrol. 17:422–32.CrossRefGoogle Scholar
  28. 28.
    Ellmers LJ, et al. (2008) Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction. Endocrinology. 149:5828–34.CrossRefGoogle Scholar
  29. 29.
    Shi Y, Massagué J. (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 113:685–700.CrossRefGoogle Scholar
  30. 30.
    Bertolino P, Deckers M, Lebrin F, ten Dijke P. (2005) Transforming growth factor-β signal transduction in angiogenesis and vascular disorders. Chest. 128:585S–90S.CrossRefGoogle Scholar
  31. 31.
    Abe H, et al. (2004) Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J. Biol. Chem. 279:14201–6.CrossRefGoogle Scholar
  32. 32.
    Matsubara T, et al. (2006) Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab. Invest. 86:357–68.CrossRefGoogle Scholar
  33. 33.
    Pannu J, Nakerakanti S, Smith E, ten Dijke P, Trojanowska M. (2007) Transforming growth factor-β receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J. Biol. Chem. 282:10405–13.CrossRefGoogle Scholar
  34. 34.
    Jones LK, et al. (2009) IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol. Dial. Transplant. 24:3024–32.CrossRefGoogle Scholar
  35. 35.
    Keophiphath M, et al. (2009) Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol. Endocrinol. 23:11–24.CrossRefGoogle Scholar
  36. 36.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. (2008) Growth factors and cytokines in wound healing. Wound Repair Regen. 16:585–601.CrossRefGoogle Scholar
  37. 37.
    Rodriguez-Iturbe B, Vaziri ND, Herrera-Acosta J, Johnson RJ. (2004) Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all. Am. J. Physiol. 286:F606–16.Google Scholar
  38. 38.
    Muller DN, et al. (2002) Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am. J. Pathol. 161:1679–93.CrossRefGoogle Scholar
  39. 39.
    Elmarakby AA, et al. (2007) Chemokine receptor 2b inhibition provides renal protection in angiotensin II-salt hypertension. Hypertension. 50:1069–76.CrossRefGoogle Scholar
  40. 40.
    Wang Y, Wang DH. (2009) Aggravated renal inflammatory responses in TRPV1 gene knockout mice subjected to DOCA-salt hypertension. Am. J. Physiol. 297:F1550–9.Google Scholar
  41. 41.
    Wang Y, Chen AF, Wang DH. (2006) Enhanced oxidative stress in kidneys of salt-sensitive hypertension: role of sensory nerves. Am. J. Physiol. 291:H3136–43.Google Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  1. 1.Central Laboratory for Basic Research in Medicine, and Division of Cardiology, First Affiliated HospitalHenan University of Traditional Chinese MedicineZhengzhouChina
  2. 2.Division of Nanomedicine and Molecular Intervention, Department of Medicine, the Neuroscience Program, and the Cell and Molecular Biology Program, B316 Clinical CenterMichigan State UniversityEast LansingUSA

Personalised recommendations