Increased Kidney Metabolism as a Pathway to Kidney Tissue Hypoxia and Damage: Effects of Triiodothyronine and Dinitrophenol in Normoglycemic Rats

  • Malou Friederich-Persson
  • Patrik Persson
  • Angelica Fasching
  • Peter Hansell
  • Lina Nordquist
  • Fredrik Palm
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 789)

Abstract

Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague–Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.

Keywords

Cellulose Catheter Filtration Polyethylene Angiotensin 

References

  1. 1.
    Nangaku M (2006) Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 17(1):17–25PubMedCrossRefGoogle Scholar
  2. 2.
    Mimura I, Nangaku M (2010) The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 6(11):667–678Google Scholar
  3. 3.
    Parascandola J (1974) Dinitrophenol and bioenergetics: an historical perspective. Mol Cell Biochem 5(1–2):69–77PubMedCrossRefGoogle Scholar
  4. 4.
    Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA et al (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415(6867):96–99PubMedCrossRefGoogle Scholar
  5. 5.
    Wrutniak-Cabello C, Casas F, Cabello G (2001) Thyroid hormone action in mitochondria. J Mol Endocrinol 26(1):67–77PubMedCrossRefGoogle Scholar
  6. 6.
    Beinhauer L (1934) Urticaria following the use of dinitrophenol. WV Med J 7:466–477Google Scholar
  7. 7.
    Imerman S, Imerman C (1936) Dinitrophenol poisoning with thrombocytopenia, granulopenia, anemia and purpura complicated by lung abscess. JAMA 106:1085–1088CrossRefGoogle Scholar
  8. 8.
    Weetman AP, Tomlinson K, Amos N, Lazarus JH, Hall R, McGregor AM (1985) Proteinuria in autoimmune thyroid disease. Acta Endocrinol (Copenh) 109(3):341–347Google Scholar
  9. 9.
    Perez-Abud R, Rodriguez-Gomez I, Villarejo AB, Moreno JM, Wangensteen R, Tassi M, et al. Salt sensitivity in experimental thyroid disorders in rats. Am J Physiol Endocrinol Metab 301(2):E281–E287Google Scholar
  10. 10.
    Evans RG, Goddard D, Eppel GA, O’Connor PM. Stability of tissue PO2 in the face of altered perfusion: a phenomenon specific to the renal cortex and independent of resting renal oxygen consumption. Clin Exp Pharmacol Physiol 38(4):247–254Google Scholar
  11. 11.
    Fine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl 65:S74–S78PubMedGoogle Scholar
  12. 12.
    Nangaku M (2004) Hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. Nephron Exp Nephrol 98(1):e8–e12PubMedCrossRefGoogle Scholar
  13. 13.
    Singh DK, Winocour P, Farrington K (2008) Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat Clin Pract Nephrol 4(4):216–226PubMedCrossRefGoogle Scholar
  14. 14.
    Palm F, Nordquist L. Renal tubulointerstitial hypoxia: cause and consequence of kidney dysfunction. Clin Exp Pharmacol Physiol 38(7):424–430Google Scholar
  15. 15.
    Hochman ME, Watt JP, Reid R, O’Brien KL (2007) The prevalence and incidence of end-stage renal disease in Native American adults on the Navajo reservation. Kidney Int 71(9):931–937PubMedCrossRefGoogle Scholar
  16. 16.
    Sayarlioglu H, Erkoc R, Dogan E, Topal C, Algun E, Erem C et al (2005) Nephropathy and retinopathy in type 2 diabetic patients living at moderately high altitude and sea level. Ren Fail 27(1):67–71PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Malou Friederich-Persson
    • 1
  • Patrik Persson
    • 1
  • Angelica Fasching
    • 1
  • Peter Hansell
    • 1
  • Lina Nordquist
    • 1
  • Fredrik Palm
    • 1
    • 2
  1. 1.Department Medical Cell Biology, Div. Integrative PhysiologyUppsala UniversityUppsalaSweden
  2. 2.Department of Medical and Health SciencesLinköping UniversityLinköpingSweden

Personalised recommendations