Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Expression and localization of GPR91 and GPR99 in murine organs

  • 1319 Accesses

  • 16 Citations

Abstract

Energy substrates and metabolic intermediates are proven ligands of a growing number of G-protein coupled receptors. In 2004, GPR91 and GPR99 were identified as receptors for the citric acid cycle intermediates, succinate and α-ketoglutarate, respectively. GPR91 seems to act as a first responder to local stress and GPR99 participates in the regulation of the acid–base balance through an intrarenal paracrine mechanism. However, a systematic analysis of the distribution of both receptors in mouse organs is still missing. The aim of this study was to examine the expression of GPR91 and GPR99 in a large number of different murine organs both at mRNA and protein level. Whereas GPR91 mRNA was detectable in almost all organs, GPR99 mRNA was mainly expressed in neuronal tissues. Widespread expression of GPR91 was also detected at the protein level by western blotting and immunohistochemistry. In addition to neuronal cells, GPR99 protein was found in renal intercalated cells and epididymal narrow cells. Double-labeling immunohistochemistry demonstrated the colocalization of GPR99 with the B1 subunit isoform of vacuolar H+-ATPases which is expressed only by a very limited number of cell types. In summary, our detailed expression analysis of GPR91 and GPR99 in murine tissues will allow a more directed search for additional functions of both receptors.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

References

  1. Ahmed SSSJ (2014) Systems biology in unruptured intracranial aneurysm: a metabolomics study in serum for the detection of biomarkers. Metabolomics 10(1):52–62

  2. Arrotéia KF, Garcia PV, Barbieri MF, Justino ML, Pereira LAV (2012) The epididymis: Embryology, structure, function and its role in fertilization and infertility, embryology - updates and highlights on classic topics. In: Prof. Luis Violin Pereira (ed) ISBN: 978-953-51-0465-0, InTech, Available from: http://www.intechopen.com/books/embryology-updates-and-highlightson-classic-topics/the-epididymis-embryology-structure-function-and-its-role-in-fertilization-and-infertility

  3. Barka T (1980) Biologically active polypeptides in submandibular glands. J Histochem Cytochem 28(8):836–859

  4. Blomqvist SR, Vidarsson H, Söder O, Enerbäck S (2006) Epididymal expression of the forkhead transcription factor Foxi1 is required for male fertility. EMBO J 25(17):4131–4141

  5. Brown D, Marshansky V (2004) Renal V-ATPase: Physiology and pathophysiology. In: Futai M, Wada Y, Kaplan JH (eds) Handbook of ATPases. Biochemistry, cell biology, pathophysiology. Wiley-VCH, Weinheim, pp 413–442

  6. Civelli O (2005) GPCR deorphanizations: the novel, the known and the unexpected transmitters. Trends Pharmacol Sci 26(1):15–19

  7. Correa PR, Kruglov EA, Thompson M, Leite MF, Dranoff JA, Nathanson MH (2007) Succinate is a paracrine signal for liver damage. J Hepatol 47(2):262–269

  8. Davis JR (1969) Metabolic aspects of spermatogenesis. Biol Reprod 1(Suppl 1):93–118

  9. Dunn WB, Broadhurst DI, Deepak SM, Buch MH, McDowell G, Spasic I, Ellis DI, Brooks N, Kell DB, Neysesc L (2007) Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate. Metabolomics 3(4):413–426

  10. Forni LG, McKinnon W, Lord GA, Treacher DF, Peron JM, Hilton PJ (2005) Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care 9(5):R591–R595

  11. He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, Chen JL, Tian H, Ling L (2004) Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429(6988):188–193

  12. Jacob M, Yusuf F, Jacob HJ (2012) Development, differentiation and derivatives of the wolffian and müllerian ducts, the human embryo. In: Dr. Yamada S (ed). p 143–166. Available from: http://www.intechopen.com/books/the-human-embryo/development-differentiation-and-derivatives-of-the-wolffian-and-m-llerian-ducts

  13. Jayasinghe NR, Cope GH, Jacob S (1990) Morphometric studies on the development and sexual dimorphism of the submandibular gland of the mouse. J Anat 172:115–127

  14. Kanaoka Y, Maekawa A, Austen KF (2013) Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand. J Biol Chem 288(16):10967–10972

  15. Kerschner JE, Hong W, Taylor SR, Kerschner JA, Khampang P, Wrege KC, North PE (2013) A novel model of spontaneous otitis media with effusion (OME) in the Oxgr1 knock-out mouse. Int J Pediatr Otorhinolaryngol 77(1):79–84

  16. Kim J, Kim YH, Cha JH, Tisher CC, Madsen KM (1999) Intercalated cell subtypes in connecting tubule and cortical collecting duct of rat and mouse. J Am Soc Nephrol 10(1):1–12

  17. Kim K, Taylor SL, Ganti S, Guo L, Osier MV, Weiss RH (2011) Urine metabolomic analysis identifies potential biomarkers and pathogenic pathways in kidney cancer. OMICS 15(5):293–303

  18. Kushnir MM, Komaromy-Hiller G, Shushan B, Urry FM, Roberts WL (2001) Analysis of dicarboxylic acids by tandem mass spectrometry. High-throughput quantitative measurement of methylmalonic acid in serum, plasma, and urine. Clin Chem 47(11):1993–2002

  19. Lee WK, Jung SM, Kwak JO, Cha SH (2006) Introduction of organic anion transporters (SLC22A) and a regulatory mechanism by Caveolins. Electrolyte Blood Press 4(1):8–17

  20. Mestrovic N, Catanzaro DF, Morris BJ (1983) Detection of renin mRNA in mouse kidney and submandibular gland by hybridization with renin cDNA. Endocrinology 113(3):1179–1181

  21. Millar RP, Newton CL (2010) The year in G protein-coupled receptor research. Mol Endocrinol 24(1):261–274

  22. Miller RL, Zhang P, Smith M, Beaulieu V, Paunescu TG, Brown D, Breton S, Nelson RD (2005) V-ATPase B1-subunit promoter drives expression of EGFP in intercalated cells of kidney, clear cells of epididymis and airway cells of lung in transgenic mice. Am J Physiol Cell Physiol 288:C1134–C1144

  23. Mühling J, Paddenberg R, Hempelmann G, Kummer W (2006) Hypobaric hypoxia affects endogenous levels of alpha-keto acids in murine heart ventricles. Biochem Biophys Res Commun 342(3):935–939

  24. Mundel P, Bachmann S, Bader M, Fischer A, Kummer W, Mayer B, Kriz W (1992) Expression of nitric oxide synthase in kidney macula densa cells. Kidney Int 42(4):1017–1019

  25. Paddenberg R, Faulhammer P, Goldenberg A, Kummer W (2006) Hypoxia-induced increase of endostatin in murine aorta and lung. Histochem Cell Biol 125(5):497–508

  26. Paddenberg R, Tiefenbach M, Faulhammer P, Goldenberg A, Gries B, Pfeil U, Lips KS, Piruat JI, López-Barneo J, Schermuly RT, Weissmann N, Kummer W (2012) Mitochondrial complex II is essential for hypoxia-induced pulmonary vasoconstriction of intra- but not of pre-acinar arteries. Cardiovasc Res 93(4):702–710

  27. Regard JB, Sato IT, Coughlin SR (2008) Anatomical profiling of G protein-coupled receptor expression. Cell 35(3):561–571

  28. Robaire B, Hinton BT, Orgebin-Crist M-C (2006) Chapter 22 – the epididymis. In: Neill JD (ed) Knobil and Neill’s physiology of reproduction, vol 1, 3rd edn. Elsevier, New York, pp 1072–1148

  29. Robben JH, Fenton RA, Vargas SL, Schweer H, Peti-Peterdi J, Deen PM, Milligan G (2009) Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells. Kidney Int 76(12):1258–1267

  30. Rodríguez-Gallego E, Guirro M, Riera-Borrull M, Hernández-Aguilera A, Mariné-Casadó R, Fernández-Arroyo S, Beltrán-Debón R, Sabench F, Hernández M, del Castillo D, Menendez JA, Camps J, Ras R, Arola L, Joven J (2015) Mapping of the circulating metabolome reveals α-ketoglutarate as a predictor of morbid obesity-associated non-alcoholic fatty liver disease. Int J Obes 39(2):279–287

  31. Rougeot C, Rosinski-Chupin I, Rougeon F (1998) Novel genes and hormones in salivary glands: from the gene for the submandibular rat 1 protein (smr1) precursor to receptor sites for smr1 mature peptides. Biomed Rev 9:17–32

  32. Sadagopan N, Li W, Roberds SL, Major T, Preston GM, Yu Y, Tones MA (2007) Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am J Hypertens 20(11):1209–1215

  33. Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH, Honoré JC, Kermorvant-Duchemin E, Varma DR, Tremblay S, Leduc M, Rihakova L, Hardy P, Klein WH, Mu X, Mamer O, Lachapelle P, Di Polo A, Beauséjour C, Andelfinger G, Mitchell G, Sennlaub F, Chemtob S (2008) The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med 14(10):1067–1076

  34. Sauter A, Machura K, Neubauer B, Kurtz A, Wagner C (2008) Development of renin expression in the mouse kidney. Kidney Int 73(1):43–51

  35. Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M (2011) Global quantification of mammalian gene expression control. Nature 473(7347):337–342

  36. Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, van der Horst GT, Hastings MH, Reppert SM (2000) Interacting molecular loops in the mammalian circadian clock. Science 288(5468):1013–1019

  37. Shum WW, Da Silva N, Brown D, Breton S (2009) Regulation of luminal acidification in the male reproductive tract via cell-cell crosstalk. J Exp Biol 212(Pt 11):1753–1761

  38. Su L, Mruk DD, Cheng CY (2011) Drug transporters, the blood-testis barrier, and spermatogenesis. J Endocrinol 208(3):207–223

  39. Takeda I, Stretch C, Barnaby P, Bhatnager K, Rankin K, Fu H, Weljie A, Jha N, Slupsky C (2009) Understanding the human salivary metabolome. NMR Biomed 22(6):577–584

  40. Tokonami N, Morla L, Centeno G, Mordasini D, Ramakrishnan SK, Nikolaeva S, Wagner CA, Bonny O, Houillier P, Doucet A, Firsov D (2013) α-Ketoglutarate regulates acid–base balance through an intrarenal paracrine mechanism. J Clin Invest 123(7):3166–3171

  41. Toma I, Kang JJ, Sipos A, Vargas S, Bansal E, Hanner F, Meer E, Peti-Peterdi J (2008) Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest 118:2526–2534

  42. Treuting PM, Dintzis SM (2012) Salivary glands. In: Treuting PM, Dintzis SM (eds) Comparative anatomy and histology – a mouse and human atlas. Elsevier, New York, p 111–120

  43. Vargas SL, Toma I, Kang JJ, Meer EJ, Peti-Peterdi J (2009) Activation of the succinate receptor GPR91 in macula densa cells causes renin release. J Am Soc Nephrol 20(5):1002–1011

  44. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A 100(8):4903–4908

  45. Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13(4):227–232

  46. Zhao L, Gao H, Lian F, Liu X, Zhao Y, Lin D (2011) 1H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin. Am J Physiol Ren Physiol 300(4):F947–F956

Download references

Author information

Correspondence to Renate Paddenberg.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 20 kb)

ESM 2

(DOCX 19 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Diehl, J., Gries, B., Pfeil, U. et al. Expression and localization of GPR91 and GPR99 in murine organs. Cell Tissue Res 364, 245–262 (2016). https://doi.org/10.1007/s00441-015-2318-1

Download citation

Keywords

  • GPR91
  • GPR99
  • Tissue distribution
  • Immunohistochemistry
  • Quantitative real time RT-PCR