Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats

Abstract mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their...

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Autores principales:	Uwe Hoff, Denise Markmann, Melina Nieminen-Kelhä, Klemens Budde, Björn Hegner
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f9b8f0a4725d450481bd8e8e941ab87f
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spelling	oai:doaj.org-article:f9b8f0a4725d450481bd8e8e941ab87f2021-12-02T18:51:01ZLow-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats10.1038/s41598-021-95790-12045-2322https://doaj.org/article/f9b8f0a4725d450481bd8e8e941ab87f2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95790-1https://doaj.org/toc/2045-2322Abstract mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes.Uwe HoffDenise MarkmannMelina Nieminen-KelhäKlemens BuddeBjörn HegnerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Uwe Hoff Denise Markmann Melina Nieminen-Kelhä Klemens Budde Björn Hegner Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
description	Abstract mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes.
format	article
author	Uwe Hoff Denise Markmann Melina Nieminen-Kelhä Klemens Budde Björn Hegner
author_facet	Uwe Hoff Denise Markmann Melina Nieminen-Kelhä Klemens Budde Björn Hegner
author_sort	Uwe Hoff
title	Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
title_short	Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
title_full	Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
title_fullStr	Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
title_full_unstemmed	Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
title_sort	low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f9b8f0a4725d450481bd8e8e941ab87f
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Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats

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