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Published on: August 19, 2020
Pathways of glomerular toxicity of cyclosporine-A: an "in vitro" study
L Castello1, P P Sainaghi, L Bergamasco
1Dipartimento di Scienze Mediche, Università degli Studi del Piemonte Orientale A. Avogadro, Novara, Italy.
Background/Aims:
Knowledge of renal toxicity of cyclosporine-A (CyA) is clouded by multiple effects on different glomerular and tubular cells and on kidney and systemic hemodynamics. To focus on glomerular action of CyA we used glomeruli isolated in vitro, with the aim of dissecting the effects on recruitment of glomerular vasoconstricting systems, like endothelin-1 (ET) and angiotensins (AI and AII).
Methods:
We studied the pathways of CyA damage on pig glomeruli isolated in vitro with the technique of sieving through mesh filters of different sizes, and incubated in an appropriate culture medium. The supernatant was sampled at different time intervals to measure ET, AI and AII concentrations upon addition of ET 10(-12) or CyA 4x10(-7)M, with or without either selective endothelin receptor A (ETA) or B (ETB), or unselective ETA-ETB receptor inhibitors.
Results:
CyA increased ET concentration (from 9.7+/-0.3 to 11.4+/-0.4 pgxml-1, p<0.002), and the added ET released AI in the medium (from 26.6+/-4.7 to 39.1+/-4.6 pgxml-1, p<0.05) when ETB receptors were blocked. In contrast, CyA stimulated angiotensins release independent of ET receptors blockade, hence, irrespective of ET concentration in the medium, from 26.6+/-4.7 to 38.0+/-2.1 pgxml-1 for AI, p<0.05, and from 12.3+/-1.0 to 14.8+/-0.9 pgxml-1 for AII, p<0.05.
Conclusion:
CyA releases ET and angiotensins independently by a direct action. Glomerular CyA toxicity might be mediated by recruitment of vasoconstricting peptides and modulated by relative ETA and ETB receptor occupancy.
Insights
Cyclosporine-A (CyA) directly triggers the release of endothelin-1 (ET) and angiotensins (AI, AII) in isolated glomeruli. This action may mediate kidney toxicity by activating vasoconstricting systems.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Cyclosporine-A (CyA) causes renal toxicity through complex mechanisms affecting glomerular and tubular cells, as well as kidney hemodynamics.
- Understanding the specific glomerular actions of CyA is crucial for elucidating its nephrotoxic effects.
- Focusing on CyA's impact on glomerular vasoconstricting systems, specifically endothelin-1 (ET) and angiotensins (AI and AII), is key.
Purpose of the Study:
- To investigate the direct effects of CyA on the release of vasoconstricting peptides (ET, AI, AII) within isolated glomeruli.
- To dissect the role of endothelin receptors (ETA and ETB) in mediating CyA-induced peptide release.
- To clarify the independent or interdependent pathways of CyA's action on these vasoactive systems.
Main Methods:
- Utilized isolated pig glomeruli incubated in vitro.
- Employed sieving techniques to isolate glomeruli and measured peptide concentrations in the supernatant over time.
- Investigated the effects of CyA and ET addition, with and without selective ETA/ETB receptor inhibitors.
Main Results:
- CyA significantly increased endothelin-1 (ET) concentration in the glomerular supernatant.
- CyA stimulated the release of angiotensin I (AI) and angiotensin II (AII) independently of ET receptor blockade.
- ET addition, when ETB receptors were blocked, led to increased AI release, suggesting a complex interplay.
Conclusions:
- Cyclosporine-A directly induces the release of both ET and angiotensins from glomeruli through independent pathways.
- Glomerular toxicity from CyA may involve the activation of vasoconstricting peptides.
- The modulation of CyA's effects could be influenced by the relative occupancy of ETA and ETB receptors.
