Abstract
Everolimus (EVL) and Sirolimus (SRL) are potent immunosuppressant agents belonging to the group of mammalian target of rapamycin (mTOR) inhibitors used to prevent transplant rejection. However, some patients develop proteinuria following a switch from a calcineurin inhibitor regimen to mTOR inhibitors. Whether different mTOR inhibitors show similar effects on podocytes is still unknown. To analyze this, human podocytes were incubated with different doses of EVL and SRL. After incubation with EVL or SRL, podocytes revealed a reduced expression of total mTOR. Phosphorylation of p70S6K and Akt was diminished, whereas pAkt expression was more reduced in the SRL group. In both groups actin cytoskeletal reorganization was increased. Synaptopodin and podocin expression was reduced as well as nephrin protein, particularly in the SRL group. NFκB activation and IL-6 levels were lower in EVL and SRL, and even lower in SRL. Apoptosis was more increased in SRL than in the EVL group. Our data suggests that mTOR inhibitors affect podocyte integrity with respect to podocyte proteins, cytoskeleton, inflammation, and apoptosis. Our study is the first to analyze both mTOR inhibitors, EVL and SRL, in parallel in podocytes. Partially, the impact of EVL and SRL on podocytes differs. Nevertheless, it still remains unclear whether these differences are of relevance regarding to proteinuria in transplant patients.
Highlights
The mechanism of action of Everolimus (EVL) and Sirolimus (SRL) is based on the inhibition of mammalian target of rapamycin, a multiprotein complex [1,2] that directly influences protein synthesis and cell cycle progression
The Puromycin aminonucleoside (PAN) group revealed the highest levels of lactate dehydrogenase (LDH) release (36.4% ± 16.8%; P < 0.001)
As shown by western blot analysis, podocytes treated with increasing concentrations (0–100 nM) of EVL or SRL for 48 h exhibited decreased expression of total mammalian target of rapamycin (mTOR) protein
Summary
The mechanism of action of Everolimus (EVL) and Sirolimus (SRL) is based on the inhibition of mammalian target of rapamycin (mTOR), a multiprotein complex [1,2] that directly influences protein synthesis and cell cycle progression. EVL and SRL are used in transplant therapy to prevent rejection. One advantage of mTOR inhibitors over calcineurin inhibitors (CNI) is that they do not induce an increase in blood pressure and only cause mild nephrotoxicity [3]. This is of clinical interest, because CNI-induced nephrotoxicity is one of the prominent side effects in kidney, as well as heart transplantations [4,5]. Proteinuria is caused by a remodelling of the glomerular filter apparatus, in particular through morphological and functional changes of the podocytes, such as cytoskeletal rearrangements and foot process effacement [12]
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