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Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala Univ, Div Integrat Physiol, Dept Med Cell Biol, Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Lund Univ, Dept Nephrol, Lund, Sweden.ORCID iD: 0000-0002-2471-6914
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
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2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 5, p. F864-F872Article in journal (Refereed) Published
Abstract [en]

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC , 2018. Vol. 314, no 5, p. F864-F872
Keywords [en]
glomerular permeability, hypoxia, mitochondrial function, mTOR, oxygen consumption, tubular injury
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-363076DOI: 10.1152/ajprenal.00033.2017ISI: 000441089200019PubMedID: 28971989OAI: oai:DiVA.org:uu-363076DiVA, id: diva2:1255427
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Society for Medical Research (SSMF)Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved

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Sivertsson, EbbaFriederich Persson, MalouFasching, AngelicaHansell, PeterPalm, Fredrik

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Sivertsson, EbbaFriederich Persson, MalouÖberg, Carl M.Fasching, AngelicaHansell, PeterPalm, Fredrik
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