Skip to main content

Advertisement

SpringerLink
Log in

Parallel regulation of renin and lysosomal integral membrane protein 2 in renin-producing cells: further evidence for a lysosomal nature of renin secretory vesicles

  • Organ physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The protease renin is the key enzyme in the renin–angiotensin system (RAS) that regulates extracellular volume and blood pressure. Renin is synthesized in renal juxtaglomerular cells (JG cells) as the inactive precursor prorenin. Activation of prorenin by cleavage of the prosegment occurs in renin storage vesicles that have lysosomal properties. To characterize the renin storage vesicles more precisely, the expression and functional relevance of the major lysosomal membrane proteins lysosomal-associated membrane protein 1 (LAMP-1), LAMP-2, and lysosomal integral membrane protein 2 (LIMP-2) were determined in JG cells. Immunostaining experiments revealed strong coexpression of renin with the LIMP-2 (SCARB2), while faint staining of LAMP-1 and LAMP-2 was detected in some JG cells only. Stimulation of the renin system (ACE inhibitor, renal hypoperfusion) resulted in the recruitment of renin-producing cells in the afferent arterioles and parallel upregulation of LIMP-2, but not LAMP-1 or LAMP-2. Despite the coregulation of renin and LIMP-2, LIMP-2-deficient mice had normal renal renin mRNA levels, renal renin and prorenin contents, and plasma renin and prorenin concentrations under control conditions and in response to stimulation with a low salt diet (with or without angiotensin-converting enzyme (ACE) inhibition). No differences in the size or number of renin vesicles were detected using electron microscopy. Acute stimulation of renin release by isoproterenol exerted similar responses in both genotypes in vivo and in isolated perfused kidneys. Renin and the major lysosomal protein LIMP-2 are colocalized and coregulated in renal JG cells, further corroborating the lysosomal nature of renin storage vesicles. LIMP-2 does not appear to play an obvious role in the regulation of renin synthesis or release.

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Abel KJ, Gross KW (1990) Physical characterization of genetic rearrangements at the mouse renin loci. Genetics 124:937–947

    PubMed  CAS  Google Scholar 

  2. Aldehni F, Tang T, Madsen K, Plattner M, Schreiber A, Friis UG, Hammond HK, Han PL, Schweda F (2011) Stimulation of renin secretion by catecholamines is dependent on adenylyl cyclases 5 and 6. Hypertension 57:460–468

    Article  PubMed  CAS  Google Scholar 

  3. Andrejewski N, Punnonen EL, Guhde G, Tanaka Y, Lullmann-Rauch R, Hartmann D, von Figura K, Saftig P (1999) Normal lysosomal morphology and function in LAMP-1-deficient mice. J Biol Chem 274:12692–12701

    Article  PubMed  CAS  Google Scholar 

  4. Balreira A, Gaspar P, Caiola D, Chaves J, Beirao I, Lima JL, Azevedo JE, Miranda MC (2008) A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome. Hum Mol Genet 17:2238–2243

    Article  PubMed  CAS  Google Scholar 

  5. Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM, Brandt SJ, Chotai D, Hodgman C, Solari RC, Lovett M, Kingsmore SF (1996) Identification of the homologous beige and Chediak–Higashi syndrome genes. Nature 382:262–265

    Article  PubMed  CAS  Google Scholar 

  6. Berkovic SF, Dibbens LM, Oshlack A, Silver JD, Katerelos M, Vears DF, Lullmann-Rauch R, Blanz J, Zhang KW, Stankovich J, Kalnins RM, Dowling JP, Andermann E, Andermann F, Faldini E, D'Hooge R, Vadlamudi L, Macdonell RA, Hodgson BL, Bayly MA, Savige J, Mulley JC, Smyth GK, Power DA, Saftig P, Bahlo M (2008) Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet 82:673–684

    Article  PubMed  CAS  Google Scholar 

  7. Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605–614

    Article  PubMed  CAS  Google Scholar 

  8. Burkhardt JK, Wiebel FA, Hester S, Argon Y (1993) The giant organelles in beige and Chediak–Higashi fibroblasts are derived from late endosomes and mature lysosomes. J Exp Med 178:1845–1856

    Article  PubMed  CAS  Google Scholar 

  9. Clark AF, Sharp MG, Morley SD, Fleming S, Peters J, Mullins JJ (1997) Renin-1 is essential for normal renal juxtaglomerular cell granulation and macula densa morphology. J Biol Chem 272:18185–18190

    Article  PubMed  CAS  Google Scholar 

  10. Desmond MJ, Lee D, Fraser SA, Katerelos M, Gleich K, Martinello P, Li YQ, Thomas MC, Michelucci R, Cole AJ, Saftig P, Schwake M, Stapleton D, Berkovic SF, Power DA (2011) Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2. Am J Physiol Renal Physiol 300:F1437–1447

    Article  PubMed  CAS  Google Scholar 

  11. Dickinson DP, Gross KW, Piccini N, Wilson CM (1984) Evolution and variation of renin genes in mice. Genetics 108:651–667

    PubMed  CAS  Google Scholar 

  12. Dittmer F, Ulbrich EJ, Hafner A, Schmahl W, Meister T, Pohlmann R, von Figura K (1999) Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phosphate receptor-deficient mice are cell type-specific. J Cell Sci 112(Pt 10):1591–1597

    PubMed  CAS  Google Scholar 

  13. Faust PL, Chirgwin JM, Kornfeld S (1987) Renin, a secretory glycoprotein, acquires phosphomannosyl residues. J Cell Biol 105:1947–1955

    Article  PubMed  CAS  Google Scholar 

  14. Friis UG, Madsen K, Stubbe J, Hansen PB, Svenningsen P, Bie P, Skott O, Jensen BL (2012) Regulation of renin secretion by renal juxtaglomerular cells. Pflugers Arch epub ahead of print

  15. Gamp AC, Tanaka Y, Lullmann-Rauch R, Wittke D, D'Hooge R, De Deyn PP, Moser T, Maier H, Hartmann D, Reiss K, Illert AL, von Figura K, Saftig P (2003) LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum Mol Genet 12:631–646

    Article  PubMed  CAS  Google Scholar 

  16. Gross KW, Gomez RA, Sigmund CD (2010) Twists and turns in the search for the elusive renin processing enzyme: focus on “Cathepsin B is not the processing enzyme for mouse prorenin”. Am J Physiol Regul Integr Comp Physiol 298:R1209–1211

    Article  PubMed  CAS  Google Scholar 

  17. Hackenthal E, Paul M, Ganten D, Taugner R (1990) Morphology, physiology, and molecular biology of renin secretion. Physiol Rev 70:1067–1116

    PubMed  CAS  Google Scholar 

  18. Jensen BL, Rasch R, Nyengaard JR, Skott O (1997) Giant renin secretory granules in beige mouse renal afferent arterioles. Cell Tissue Res 288:399–406

    Article  PubMed  CAS  Google Scholar 

  19. Kuronita T, Eskelinen EL, Fujita H, Saftig P, Himeno M, Tanaka Y (2002) A role for the lysosomal membrane protein LGP85 in the biogenesis and maintenance of endosomal and lysosomal morphology. J Cell Sci 115:4117–4131

    Article  PubMed  CAS  Google Scholar 

  20. Kurtz A, Schweda F (2006) Osmolarity-induced renin secretion from kidneys: evidence for readily releasable renin pools. Am J Physiol Renal Physiol 290:F797–805

    Article  PubMed  CAS  Google Scholar 

  21. Matsuba H, Watanabe T, Watanabe M, Ishii Y, Waguri S, Kominami E, Uchiyama Y (1989) Immunocytochemical localization of prorenin, renin, and cathepsins B, H, and L in juxtaglomerular cells of rat kidney. J Histochem Cytochem 37:1689–1697

    Article  PubMed  CAS  Google Scholar 

  22. Mercure C, Lacombe MJ, Khazaie K, Reudelhuber TL (2010) Cathepsin B is not the processing enzyme for mouse prorenin. Am J Physiol Regul Integr Comp Physiol 298:R1212–1216

    Article  PubMed  CAS  Google Scholar 

  23. Mullins LJ, Payne CM, Kotelevtseva N, Brooker G, Fleming S, Harris S, Mullins JJ (2000) Granulation rescue and developmental marking of juxtaglomerular cells using “piggy-BAC” recombination of the mouse ren locus. J Biol Chem 275:40378–40384

    Article  PubMed  CAS  Google Scholar 

  24. Pentz ES, Lopez ML, Kim HS, Carretero O, Smithies O, Gomez RA (2001) Ren1d and Ren2 cooperate to preserve homeostasis: evidence from mice expressing GFP in place of Ren1d. Physiol Genomics 6:45–55

    PubMed  CAS  Google Scholar 

  25. Peters J, Clausmeyer S (2002) Intracellular sorting of renin: cell type specific differences and their consequences. J Mol Cell Cardiol 34:1561–1568

    Article  PubMed  CAS  Google Scholar 

  26. Peters J, Munter K, Bader M, Hackenthal E, Mullins JJ, Ganten D (1993) Increased adrenal renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation by cAMP, angiotensin II, and calcium. J Clin Invest 91:742–747

    Article  PubMed  CAS  Google Scholar 

  27. Peti-Peterdi J, Fintha A, Fuson AL, Tousson A, Chow RH (2004) Real-time imaging of renin release in vitro. Am J Physiol Renal Physiol 287:F329–335

    Article  PubMed  CAS  Google Scholar 

  28. Reczek D, Schwake M, Schroder J, Hughes H, Blanz J, Jin X, Brondyk W, Van Patten S, Edmunds T, Saftig P (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131:770–783

    Article  PubMed  CAS  Google Scholar 

  29. Saftig P, Klumperman J (2009) Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10:623–635

    Article  PubMed  CAS  Google Scholar 

  30. Schröder B, Wrocklage C, Pan C, Jager R, Kosters B, Schafer H, Elsasser HP, Mann M, Hasilik A (2007) Integral and associated lysosomal membrane proteins. Traffic 8:1676–1686

    Article  PubMed  Google Scholar 

  31. Schweda F, Kurtz A (2011) Regulation of renin release by local and systemic factors. Rev Physiol Biochem Pharmacol 161:1–44

    PubMed  CAS  Google Scholar 

  32. Schweda F, Riegger GA, Kurtz A, Kramer BK (2000) Store-operated calcium influx inhibits renin secretion. Am J Physiol Renal Physiol 279:F170–176

    PubMed  CAS  Google Scholar 

  33. Schweda F, Wagner C, Kramer BK, Schnermann J, Kurtz A (2003) Preserved macula densa-dependent renin secretion in A1 adenosine receptor knockout mice. Am J Physiol Renal Physiol 284:F770–777

    PubMed  CAS  Google Scholar 

  34. Sharp MG, Fettes D, Brooker G, Clark AF, Peters J, Fleming S, Mullins JJ (1996) Targeted inactivation of the Ren-2 gene in mice. Hypertension 28:1126–1131

    Article  PubMed  CAS  Google Scholar 

  35. Sigmund CD, Gross KW (1991) Structure, expression, and regulation of the murine renin genes. Hypertension 18:446–457

    Article  PubMed  CAS  Google Scholar 

  36. Soltesz BM, Gomba S, Szokol M (1979) Lysosomal enzymes in the juxtaglomerular cell granules. Experientia 35:533–534

    Article  PubMed  CAS  Google Scholar 

  37. Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, Janssen PM, Blanz J, von Figura K, Saftig P (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–906

    Article  PubMed  CAS  Google Scholar 

  38. Taugner R, Hackenthal E (1988) On the character of the secretory granules in juxtaglomerular epithelioid cells. Int Rev Cytol 110:93–131

    Article  PubMed  CAS  Google Scholar 

  39. Taugner R, Whalley A, Angermuller S, Buhrle CP, Hackenthal E (1985) Are the renin-containing granules of juxtaglomerular epithelioid cells modified lysosomes? Cell Tissue Res 239:575–587

    Article  PubMed  CAS  Google Scholar 

  40. Wagner C, de Wit C, Kurtz L, Grünberger C, Kurtz A, Schweda F (2007) Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 100:556–563

    Article  PubMed  CAS  Google Scholar 

  41. Waheed A, Gottschalk S, Hille A, Krentler C, Pohlmann R, Braulke T, Hauser H, Geuze H, von Figura K (1988) Human lysosomal acid phosphatase is transported as a transmembrane protein to lysosomes in transfected baby hamster kidney cells. Embo J 7:2351–2358

    PubMed  CAS  Google Scholar 

  42. Yanai K, Saito T, Kakinuma Y, Kon Y, Hirota K, Taniguchi-Yanai K, Nishijo N, Shigematsu Y, Horiguchi H, Kasuya Y, Sugiyama F, Yagami K, Murakami K, Fukamizu A (2000) Renin-dependent cardiovascular functions and renin-independent blood–brain barrier functions revealed by renin-deficient mice. J Biol Chem 275:5–8

    Article  PubMed  CAS  Google Scholar 

  43. Zachos C, Blanz J, Saftig P, Schwake M (2012) A critical histidine residue within LIMP-2 mediates pH sensitive binding to its ligand beta-glucocerebrosidase. Traffic 13:1113–1123

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The expert technical assistance of Katharina Ehm, Marlies Hamann, Regine Volkmann, and Frieda Webinger is gratefully acknowledged. Confocal and electron microscopy were performed in the imaging center of the Collaborative Research Center 699, University of Regensburg (SFB699, Anita Zügner, Uwe de Vries). This study was financially supported by the Deutsche Forschungsgemeinschaft (SFB699 to F.S. and GRK1459 to M.S. and P.S).

Author information

Authors and Affiliations

  1. Institut für Physiologie, Universität Regensburg, 93040, Regensburg, Germany

    Johannes Schmid & Frank Schweda

  2. Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, 24098, Kiel, Germany

    Miriam Oelbe, Paul Saftig & Michael Schwake

Authors
  1. Johannes Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam Oelbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Saftig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Schwake
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank Schweda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Schweda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmid, J., Oelbe, M., Saftig, P. et al. Parallel regulation of renin and lysosomal integral membrane protein 2 in renin-producing cells: further evidence for a lysosomal nature of renin secretory vesicles. Pflugers Arch - Eur J Physiol 465, 895–905 (2013). https://doi.org/10.1007/s00424-012-1192-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-012-1192-x

Keywords

Search

Navigation