Abstract
Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkANTR and p75NTR. Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a down-regulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an up-regulation of p75 NTR and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75NTR down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A.
Highlights
Nerve growth factor (NGF) is a neurotrophin produced and released by a number of different mammalian cells acting on cell survival and differentiation, tissue repair and inflammatory responses [1]
Our results showed that the protein expression levels of NGF begin to increase upon 10nM Cyclosporine A (CsA) treatment (+ 30 ± 3.45%) and that the up-regulation was maintained up to 8μM (+110 ± 15.0%) (Figure 1 B)
As expected, using nuclear and cytosolic extracts obtained from HK-2 cells exposed to short treatment with CsA, we observed that CNI increased cytosolic inactivated NFATc1 content up to 220 ± 12.0 %, reducing the nuclear activated fraction (-33.2 ± 3.42 %,Figure 1C)
Summary
Nerve growth factor (NGF) is a neurotrophin produced and released by a number of different mammalian cells acting on cell survival and differentiation, tissue repair and inflammatory responses [1]. A specific cell-surface TrkA NTR / p75NTR ratio seems to be directly responsible for either proliferative and/or survival effects (TrkA NTR) or apoptotic responses (p75 NTR), with p75NTR acting alone or in combination to modulate TrkA NTR trafficking and/or signaling [2]. We previously reported elevated serum NGF levels in patients affected by glomerulonephritis, chronic kidney disease and end-stage renal disease even though we did not explore the significance of our findings [3]. In a cohort of renal transplant recipients we found higher NGF serum levels respect to healthy controls [4]. The observed NGF levels were higher than those detected in other kidney diseases investigated [3,4]
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