Skip to main content

Bj-PRO-5a and Bj-PRO 10c Found at C-Type Natriuretic Peptide Precursor of Bothrops jararaca Change Renal Function of Hypertensive Rats

Abstract

Proline-rich oligopeptides from Bothrops jararaca (Bj-PROs) produce potent and long-lasting antihypertensive effect through mechanisms that go beyond ACE inhibition. In this study we evaluated the renal function parameters of spontaneously hypertensive rats (SHR) injected with Bj-PRO-5a and -10c (0.47, 71 or 710 nmol/kg) found in the CNP-precursor of the snake. At 71 and 710 nmol/kg, Bj-PROs increased urinary flow rate (18.1–43.5%). At 71 nmol/kg, Bj-PRO 5a and 10c elevated sodium excretion (68.1 and 40.9%, respectively) and Bj-PRO-5a also increased urinary sodium/creatinine ratio (56.5%). At 0.47 nmol/kg, Bj-PROs did not change renal function. All doses of Bj-PROs reduced blood pressure (Δ = −13 to −24mmHg). We conclude that Bj-PROs reduce blood pressure and improve renal function of SHRs through diuretic and natriuretic mechanisms.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

ACE:

Angiotensin I converting enzyme

AS:

Argininosuccinate synthatase

Bj :

Bothrops jararaca

CNP:

C-type natriuretic peptide

Cr:

Creatinine

GFR:

Glomerular filtration rate

Na:

Sodium

NO:

Nitric oxide

PRO:

Proline rich oligopeptide

SBP:

Systolic blood pressure

SHR:

Spontaneously hypertensive rat

References

  • Bakhle YS (1971) Inhibition of angiotensin I converting enzyme by venom peptides. Br J Pharmacol 43:252–254

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Bourque CW, Oliet SH, Richard D (1994) Osmoreceptors, osmoreception, and osmoregulation. Front Neuroendocrinol 15:231–274. doi:10.1006/frne.1994.1010

    CAS  Article  PubMed  Google Scholar 

  • Camargo AC, Ianzer D, Guerreiro JR, Serrano SM (2012) Bradykinin-potentiating peptides: beyond captopril. Toxicon 59:516–523. doi:10.1016/j.toxicon.2011.07.013

    CAS  Article  PubMed  Google Scholar 

  • Coleman TG, Manning RD Jr, Norman RA Jr, DeClue J (1975) The role of the kidney in spontaneous hypertension. Am Heart J 89:94–98

    CAS  Article  PubMed  Google Scholar 

  • Guerreiro JR et al (2009) Argininosuccinate synthetase is a functional target for a snake venom anti-hypertensive peptide: role in arginine and nitric oxide production. J Biol Chem 284:20022–20033. doi:10.1074/jbc.M109.021089

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hayashi MA et al (2003) The C-type natriuretic peptide precursor of snake brain contains highly specific inhibitors of the angiotensin-converting enzyme. J Neurochem 85:969–977

    CAS  Article  PubMed  Google Scholar 

  • Ianzer D et al (2007) Do the cardiovascular effects of angiotensin-converting enzyme (ACE) I involve ACE-independent mechanisms? new insights from proline-rich peptides of Bothrops jararaca J Pharmacol Exp Ther 322:795–805. doi:10.1124/jpet.107.120873

    CAS  Article  PubMed  Google Scholar 

  • Ianzer D et al (2011) BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect. Ther Adv Cardiovasc Dis. doi:10.1177/1753944711427318

    PubMed  Google Scholar 

  • Jovanovic D, Dimitrijevic J, Varagic J, Jovovic D, Starcevic A, Djukanovic L (1998) Effects of captopril on morphologic changes in kidney of spontaneously hypertensive rats with adriamycin nephropathy. Ren Fail 20:451–458

    CAS  Article  PubMed  Google Scholar 

  • Ketteler M, Ritz E (2000) Renal failure: a state of nitric oxide deficiency? Kidney Int 58:1356–1357. doi:10.1046/j.1523-1755.2000.00294.x

    CAS  Article  PubMed  Google Scholar 

  • Moe GW, Legault L, Skorechi KL (1991) Control of Extracelular Fluid Volume and Phatophysiology of Edema Formation. In: Saunders W, Brenner BM, Rector FC (eds) The Kidney. 4th edn., Elsevier, Philadelphia, pp 623–676

    Google Scholar 

  • Morais KL et al (2013) Proline rich-oligopeptides: diverse mechanisms for antihypertensive action. Peptides 48:124–133. doi:10.1016/j.peptides.2013.07.016

    CAS  Article  PubMed  Google Scholar 

  • Ondetti MA, Rubin B, Cushman DW (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196:441–444

    CAS  Article  PubMed  Google Scholar 

  • Paschoal JF et al (2014) Insights into cardiovascular effects of proline-rich oligopeptide (Bj-PRO-10c) revealed by structure-activity analyses: dissociation of antihypertensive and bradycardic effects. Amino Acids 46:401–413. doi:10.1007/s00726-013-1630-x

    CAS  Article  PubMed  Google Scholar 

  • Roman RJ, Cowley AW, Jr. (1985) Abnormal pressure-diuresis-natriuresis response in spontaneously hypertensive rats Am J Physiol 248:F199–F205

    Google Scholar 

  • Roysommuti S, Mozaffari MS, Berecek KH, Wyss JM (1999) Lifetime treatment with captopril improves renal function in spontaneously hypertensive rats. Clin Exp Hypertens 21:1315–1325

    CAS  Article  PubMed  Google Scholar 

  • Silva CA, Ianzer DA, Portaro FC, Konno K, Faria M, Fernandes BL, Camargo AC (2008a) Characterization of urinary metabolites from four synthetic bradykinin potentiating peptides (BPPs) in mice. Toxicon 52:501–507. doi:10.1016/j.toxicon.2008.06.024

  • Silva CA et al (2008b) Tissue distribution in mice of BPP 10c, a potent proline-rich anti-hypertensive peptide of Bothrops jararaca. Toxicon 51:515–523. doi:10.1016/j.toxicon.2007.11.003

  • Tashima AK et al (2012) Peptidomics of three Bothrops snake venoms: insights into the molecular diversification of proteomes and peptidomes. Mol Cell Proteomics 11:1245–1262. doi:10.1074/mcp.M112.019331

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—CAT/Cepid, proc 98/14307-9 and Post-doctoral fellow proc. 08/54820-0); Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG—DCR 14/2013 and DOCFix 04/2014); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Pessoal de Nivel Superior (CAPES—Edital Toxinologia 63/2010—AUXPE 1593/2011).

Author Contributions

Participated in research design: DI, CHX, DAC-Jr and ACMC; Conducted experiments: JRRM, JY, KDD, CHX and DI; Contributed with new reagents or analytic tools: MMT, ACS, RASS and ACMC; Performed data analysis: CHX and DI; Wrote or contributed to the writing of the manuscript: CHX and DI.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Danielle Ianzer.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xavier, C.H., Miranda, J.R.R., Yamaguchi, J. et al. Bj-PRO-5a and Bj-PRO 10c Found at C-Type Natriuretic Peptide Precursor of Bothrops jararaca Change Renal Function of Hypertensive Rats. Int J Pept Res Ther 23, 381–385 (2017). https://doi.org/10.1007/s10989-017-9575-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10989-017-9575-7

Keywords

  • Bj-PROs
  • Blood pressure
  • Bradykinin-potentiating peptides
  • Heart rate
  • Hypertension
  • Proline-rich oligopeptides
  • Renal function