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Cellular effects of everolimus and sirolimus on podocytes
Sandra Müller-Krebs1, Lena Weber, Julia Tsobaneli
1Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
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.
Insights
Mammalian target of rapamycin (mTOR) inhibitors like everolimus and sirolimus impact kidney podocyte integrity. These immunosuppressants affect podocyte proteins, cytoskeleton, inflammation, and apoptosis, with differing effects observed between the two drugs.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Mammalian target of rapamycin (mTOR) inhibitors are crucial for preventing transplant rejection.
- Proteinuria can occur after switching immunosuppressants from calcineurin inhibitors to mTOR inhibitors.
- The distinct effects of everolimus (EVL) and sirolimus (SRL) on podocytes remain unclear.
Purpose of the Study:
- To investigate and compare the effects of everolimus (EVL) and sirolimus (SRL) on human podocytes.
- To analyze the impact of these mTOR inhibitors on podocyte protein expression, cytoskeleton, inflammation, and apoptosis.
Main Methods:
- Human podocytes were incubated with varying doses of EVL and SRL.
- Expression of key podocyte proteins (mTOR, p70S6K, Akt, synaptopodin, podocin, nephrin) was measured.
- NFκB activation, IL-6 levels, and apoptosis were assessed.
Main Results:
- Both EVL and SRL reduced total mTOR expression and p70S6K/Akt phosphorylation.
- Actin cytoskeletal reorganization increased in both groups.
- Podocyte protein expression (synaptopodin, podocin, nephrin) and NFκB/IL-6 levels decreased, more so with SRL.
- Apoptosis was significantly higher in the SRL group.
Conclusions:
- mTOR inhibitors (EVL and SRL) impact human podocyte integrity, affecting proteins, cytoskeleton, inflammation, and apoptosis.
- EVL and SRL exhibit partially different effects on podocytes.
- The clinical relevance of these observed differences regarding proteinuria in transplant patients requires further investigation.
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