Sivertsson 2017 Am J Physiol Renal Physiol
|Sivertsson E, Friederich-Persson M, Öberg CM, Fasching A, Hansell P, Rippe B, Palm F (2017) Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability. Am J Physiol Renal Physiol 314:F864-F872.|
Abstract: Increased kidney oxygen consumption causing tissue hypoxia is suggested as a common pathway to chronic kidney disease. 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. We therefore 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 studied fourteen 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 to 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 to development of chronic kidney disease, mTOR inhibition to patients with pre-existing nephropathy should be used with caution since it may accelerate the progression of disease.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes
Organism: Rat Tissue;cell: Kidney Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: N HRR: Oxygraph-2k
Labels, 2018-01, Rapamycin