mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside.
Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study, we investigated whether glomerular permeability can be acutely altered by the mTORi temsirolimus and whether mTORi can affect acute puromycin aminonucleoside (PAN) or angiotensin II (ANG II)-induced glomerular hyperpermeability. In anesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Temsirolimus was administered as a single intravenous dose 30 min before the start of the experiments in animals infused with PAN or ANG II or in nonexposed animals. Polydispersed FITC-Ficoll-70/400 (molecular radius 10-80 Å) and (51)Cr-EDTA infusion was given during the whole experiment. Measurements of Ficoll in plasma and urine were performed sequentially before the temsirolimus injection (baseline) and at 5, 15, 30, 60, and 120 min after the start of the experiments. Urine and plasma samples were analyzed by high-performance size-exclusion chromatography (HPSEC) to assess glomerular sieving coefficients (θ) for Ficoll10-80Å. Temsirolimus per se increased baseline glomerular permeability to Ficoll50-80Å 45 min after its administration, a reactive oxygen species (ROS)-dependent phenomenon. PAN caused a rapid and reversible increase in glomerular permeability, peaking at 5 min, and again at 60-120 min, which could be blocked by the ROS scavenger tempol. mTORi abrogated the second permeability peak induced by PAN. However, it had no effect on the immediate ANG II- or PAN-induced increases in glomerular permeability.
Department of Nephrology, Lund University, Lund, Sweden.
Josefin
J
Axelsson
Department of Nephrology, Lund University, Lund, Sweden Bengt.Rippe@med.lu.se.
Anna
A
Rippe
Department of Nephrology, Lund University, Lund, Sweden.
Bengt
B
Rippe
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D023421:Models, Animal; D011692:Puromycin Aminonucleoside / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013113:Spin Labels; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013997:Time Factors
D003497:Cyclic N-Oxides; D013113:Spin Labels; D000804:Angiotensin II; D011692:Puromycin Aminonucleoside; C401859:temsirolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; C001803:tempol; D020123:Sirolimus
glomerular endothelium; glomerular filtration; podocytes; proteinuria; transplantation