Identification and Distribution of Uncoupling Protein Isoforms in the Normal and Diabetic Rat Kidney

  • Malou Friederich
  • Lina Nordquist
  • Johan Olerud
  • Magnus Johansson
  • Peter Hansell
  • Fredrik Palm
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 645)


Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively.

UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls.

In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.


Brown Adipose Tissue Uncouple Protein Proximal Tubular Cell Diabetic Kidney Kidney Cortex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    T. Nishikawa, D. Edelstein, and M. Brownlee, The missing link: a single unifying mechanism for diabetic complications, Kidney Int Suppl 77(S26-30 (2000).PubMedCrossRefGoogle Scholar
  2. 2.
    R. P. Robertson, Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes, J Biol Chem 279(41), 42351-4 (2004).PubMedCrossRefGoogle Scholar
  3. 3.
    M. Brownlee, Biochemistry and molecular cell biology of diabetic complications, Nature 414(6865), 813-20 (2001).PubMedCrossRefGoogle Scholar
  4. 4.
    B. B. Lowell, and G. I. Shulman, Mitochondrial dysfunction and type 2 diabetes, Science 307(5708), 384-7 (2005).PubMedCrossRefGoogle Scholar
  5. 5.
    S. S. Korshunov, V. P. Skulachev, and A. A. Starkov, High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria, FEBS Lett 416(1), 15-8 (1997).PubMedCrossRefGoogle Scholar
  6. 6.
    S. S. Liu, Generating, partitioning, targeting and functioning of superoxide in mitochondria, Biosci Rep 17(3), 259-72 (1997).PubMedCrossRefGoogle Scholar
  7. 7.
    M. D. Brand, Uncoupling to survive? The role of mitochondrial inefficiency in ageing, Exp Gerontol 35(6-7), 811-20 (2000).PubMedCrossRefGoogle Scholar
  8. 8.
    T. Nishikawa, D. Edelstein, X. L. Du, S. Yamagishi, T. Matsumura, Y. Kaneda, M. A. Yorek, D. Beebe, P. J. Oates, H. P. Hammes, I. Giardino, and M. Brownlee, Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage, Nature 404(6779), 787-90 (2000).PubMedCrossRefGoogle Scholar
  9. 9.
    P. Jezek, Possible physiological roles of mitochondrial uncoupling proteins–UCPn, Int J Biochem Cell Biol 34(10), 1190-206 (2002).PubMedCrossRefGoogle Scholar
  10. 10.
    A. G. Dulloo, and S. Samec, Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered, Br J Nutr 86(2), 123-39 (2001).PubMedCrossRefGoogle Scholar
  11. 11.
    A. Negre-Salvayre, C. Hirtz, G. Carrera, R. Cazenave, M. Troly, R. Salvayre, L. Penicaud, and L. Casteilla, A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation, Faseb J 11(10), 809-15 (1997).PubMedGoogle Scholar
  12. 12.
    C. Duval, A. Negre-Salvayre, A. Dogilo, R. Salvayre, L. Penicaud, and L. Casteilla, Increased reactive oxygen species production with antisense oligonucleotides directed against uncoupling protein 2 in murine endothelial cells, Biochem Cell Biol 80(6), 757-64 (2002).PubMedCrossRefGoogle Scholar
  13. 13.
    K. S. Echtay, E. Winkler, K. Frischmuth, and M. Klingenberg, Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone), Proc Natl Acad Sci U S A 98(4), 1416-21 (2001).PubMedCrossRefGoogle Scholar
  14. 14.
    A. M. Vincent, J. A. Olzmann, M. Brownlee, W. I. Sivitz, and J. W. Russell, Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death, Diabetes 53(3), 726-34 (2004).PubMedCrossRefGoogle Scholar
  15. 15.
    F. Palm, J. Cederberg, P. Hansell, P. Liss, and P. O. Carlsson, Reactive oxygen species cause diabetesinduced decrease in renal oxygen tension, Diabetologia 46(8), 1153-60 (2003).PubMedCrossRefGoogle Scholar
  16. 16.
    M. Friederich, J. Olerud, A. Fasching, P. Liss, P. Hansell, and F. Palm, Uncoupling protein 2 in diabetic kidneys: Increased protein expression correlates to increased non-transport related oxygen consumption, Adv Exp Med Biol In press((2007).Google Scholar
  17. 17.
    A. Tojo, M. Kimoto, and C. S. Wilcox, Renal expression of constitutive NOS and DDAH: separate effects of salt intake and angiotensin, Kidney Int 58(5), 2075-83 (2000).PubMedCrossRefGoogle Scholar
  18. 18.
    F. Palm, and P. O. Carlsson, Thick ascending tubular cells in the loop of Henle: regulation of electrolyte homeostasis, Int J Biochem Cell Biol 37(8), 1554-9 (2005).PubMedCrossRefGoogle Scholar
  19. 19.
    F. Palm, P. Hansell, G. Ronquist, A. Waldenstrom, P. Liss, and P. O. Carlsson, Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats, Diabetologia 47(7), 1223-31 (2004).PubMedCrossRefGoogle Scholar
  20. 20.
    A. Korner, A. C. Eklof, G. Celsi, and A. Aperia, Increased renal metabolism in diabetes. Mechanism and functional implications, Diabetes 43(5), 629-33 (1994).PubMedCrossRefGoogle Scholar
  21. 21.
    F. Palm, L. Nordquist, and D. G. Buerk, Nitric oxide in the kidney; direct measurements of bioavailable renal nitric oxide, Adv Exp Med Biol 599(117-23 (2007).PubMedCrossRefGoogle Scholar
  22. 22.
    K. S. Echtay, D. Roussel, J. St-Pierre, M. B. Jekabsons, S. Cadenas, J. A. Stuart, J. A. Harper, S. J. Roebuck, A. Morrison, S. Pickering, J. C. Clapham, and M. D. Brand, Superoxide activates mitochondrial uncoupling proteins, Nature 415(6867), 96-9 (2002).PubMedCrossRefGoogle Scholar
  23. 23.
    K. S. Echtay, T. C. Esteves, J. L. Pakay, M. B. Jekabsons, A. J. Lambert, M. Portero-Otin, R. Pamplona, A. J. Vidal-Puig, S. Wang, S. J. Roebuck, and M. D. Brand, A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling, Embo J 22(16), 4103-10 (2003).PubMedCrossRefGoogle Scholar
  24. 24.
    F. Palm, D. G. Buerk, P. O. Carlsson, P. Hansell, and P. Liss, Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation, Diabetes 54(11), 3282-7 (2005).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Malou Friederich
    • 1
  • Lina Nordquist
    • 1
  • Johan Olerud
    • 1
  • Magnus Johansson
    • 2
  • Peter Hansell
    • 1
  • Fredrik Palm
    • 1
    • 3
  1. 1.Department of Medical Cell Biology, BMC, PO 571Uppsala UniversitySweden
  2. 2.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of MedicineGeorgetown UniversityWashingtonUSA

Personalised recommendations