Mitogen-Activated Protein Kinase 14 Promotes AKI

Abstract

An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFB DNA binding heterodimer RelB/NFB2, and proteins involved in NFB2 p100 ubiquitination and proteasomal processing to p52, as upregulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in acute folate nephropathy and human AKI. , kidney expression levels of NFB2 p100 and p52 increased rapidly after folic acid injection, as did DNA binding of RelB and NFB2, detected in nuclei isolated from the kidneys. Compared with wild-type mice, MAP3K14 activity-deficient aly/aly (MAP3K14) mice had less kidney dysfunction, inflammation, and apoptosis in acute folate nephropathy and less kidney dysfunction and a lower mortality rate in cisplatin-induced AKI. The exchange of bone marrow between wild-type and MAP3K14 mice did not affect the survival rate of either group after folic acid injection. In cultured tubular cells, MAP3K14 small interfering RNA targeting decreased inflammation and cell death. Additionally, cell culture and studies identified the chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets in tubular cells. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.

Chronodisruption: A Poorly Recognized Feature of CKD

“…TWEAK is a proinflammatory cytokine of the TNF superfamily that promotes AKI and CKD [67,68]. A key feature of the TWEAK cytokine is that, contrary to TNF, it recruits the NIK-mediated, non-canonical pathway for activation of the NFκB transcription factor in kidney cells on top of the canonical pathway for NFκB activation [69][70][71][72][73]. NFκB is a key proinflammatory transcription factor that also downregulates kidney protective molecules [74].…”

Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms

“…In renal cells, cytokines activate a host of signaling pathways, transcription factors, and epigenetic mechanisms to regulate gene expression. A key transcription factor promoting kidney inflammation is NF-B, which is activated by either the canonical or the noncanonical pathway (73,101). Functional in vivo studies have characterized the contribution of certain epigenetic mechanisms to kidney injury, including DNA methylation, histone acetylation, methylation or crotonylation, and miRNAs (8,42,86,90,120).…”

TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets?

“…As compared with TRAIL and OPG, there is much more information on the actions of TWEAK and Fn14 on the kidney. Table 2 summarizes the effects that TWEAK has on different kidney cells in vitro [140], where it promotes fibrosis, inflammation, proliferation, as well as cell death [81,85,94,96,109,110,114,115,[141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159]. In line with these effects, in vivo studies suggest that TWEAK/Fn14 blockade might protect against renal injury/disease ( Table 2).…”

“…Renal fibroblasts Decrease in collagen I and fibronectin protein levels [143] Inflammation Tubular cells MCP-1, RANTES increase via NF-κB and JAK2 kinase activation [144] MCP-1, RANTES, and IL-6 increase [145] CCL21 increase via non-canonical NF-κB activation [96] CXCL16 increase via NF-κB [146] CD74 and DDT increase [147] IL-6 and other chemokines via EGFR activation, ERK activation [148] CXCL10 increase via MAP3K14 and non-canonical NF-κB pathway [149] Modulation of NF-κB components Bcl3 overexpression -which decreases NF-κB transcriptional activity [150] Modulation of NF-κB components: NF-kBiz overexpression -which has anti-inflammatory anti-apoptotic effects [151] Podocytes MCP-1 increase via NF-κB [152] CCL19, RANTES increase via NF-κB [153] CCL21 increase via non-canonical NF-κB pathway Induction of multiple inflammatory cytokines/chemokines and adhesion molecules [110] Renal fibroblasts MCP-1 and RANTES increase via NF-κB [143] Mesangial cells IL-6, IL-8, MCP-1, and CCL5 increase via NF-κB [ 8 5 ] Induction of multiple inflammatory cytokines/chemokines and adhesion molecules [110] MCP-1, RANTES, CXCL10, and CXCL1 increase [109] Proliferation Tubular cells Cell number increase, cyclin D1 expression via MAPK (ERK/p38), PI3K/Akt, NF-κB [114] Mesangial cells Promotion of cell proliferation and cell cycle activity [85] Renal fibroblasts Increase in mitosis number, cyclin D1 expression via Ras/ERK pathway [143] Cell death Tubular cells (Late) Necroptosis via RIPK1, RIPK3, MLKL [154] Apoptosis and increased inflammatory gene expression [155] In an inflammatory milieu, induction of apoptosis, activation of caspase-8, -9 -3, Bid cleavage and mitochondrial injury [115] Others Tubular cells Klotho down-regulation via NF-κB [156] MAGED2 up-regulation -modulation of electrolyte transport [157] PGC-1alpha and mitochondrial function down-regulation [158] Endothelial cells Endothelin-1 increase and ECE1 up-regulation via AP-1 and NF-kB [159] Cell growth and migration, enhanced FGF-2 and VEGF-A mitogenic activity [81]<...>…”