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Tubular TNFSF4/OX40L promotes fibrotic transition following acute kidney injury via activating GSK-3α
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DOI：10.1016/j.phrs.2026.108230.png)
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Abstract
En 中文
Acute kidney injury (AKI) often progresses to chronic kidney disease (CKD) characterized by renal fibrosis, yet the regulatory mechanisms driving this transition remain elusive. Here, it is demonstrated that tumor necrosis factor superfamily member 4 (TNFSF4/OX40L) significantly upregulates in proximal tubular cells (PTCs) from patients with CKD and in murine models of AKI-CKD transition induced by unilateral ischemia-reperfusion injury (uIRI) or repeated low-dose cisplatin. Elevated TNFSF4 levels correlates positively with the severity of tubulointerstitial injury and negatively with estimated glomerular filtration rate. Functionally, proximal tubule-specific deletion of Tnfsf4 markedly ameliorates tubular damage, renal inflammation and interstitial fibrosis in both AKI-CKD models. Furthermore, anti-TNFSF4 monoclonal antibody exerts its therapeutic effects in AKI-CKD mice suffering from uIRI. Conversely, overexpression of TNFSF4 exacerbates pro-fibrotic responses in PTCs under TGF-β1 or chronic hypoxia conditions. Mechanistically, immunoprecipitation-mass spectrometry identifies an interaction between TNFSF4 and glycogen synthase kinase-3α (GSK-3α). TNFSF4 blocks synaptotagmin-like protein 4 (SYTL4)-mediated ubiquitination of GSK-3α, prolongs its half-life, and sustains profibrotic signaling, effects reversed by GSK-3α knockdown. Collectively, these results uncover a previously unrecognized TNFSF4-GSK-3α axis as a key proximal tubule-intrinsic driver of AKI-CKD progression, and propose targeting this pathway as a promising therapeutic strategy to mitigate renal fibrosis and halt AKI-CKD transition.
Keywords:
AKI
acute kidney injury
BAX
BCL2 Associated X Protein
BUN
blood urea nitrogen
CHX
cycloheximide
CKD
chronic kidney disease
Co-IP
co-immunoprecipitation
CQ
chloroquine
eGFR
estimated glomerular filtration rate
ESRD
end-stage renal disease
FBs
fibroblasts
FN
fibronectin
GSK-3α
glycogen synthase kinase-3α
HE
hematoxylin-eosin
IF
immunofluorescence
IFTA
interstitial fibrosis and tubular atrophy
IHC
immunohistochemistry
IL-18
interleukin-18
IL-1β
interleukin-1β
IL-6
interleukin-6
IP-MS
immunoprecipitation–mass spectrometry
KIM-1
kidney injury molecule-1
LTL
Lotus Tetragonolobus Lectin
mAb
monoclonal antibody
NGAL
neutrophil gelatinase associated lipocalin
PAS
periodic acid-Schiff
PCR
polymerase chain reaction
PT
proximal tubule
PTCs
proximal tubular epithelial cells
RLDC
repeated low-dose cisplatin
RT-qPCR
real-time quantitative PCR
Scr
serum creatinine
SD
standard deviation
SMURF1
Smad ubiquitin regulatory factor 1
SYTL4
synaptotagmin-like 4
TNFSF4
tumor necrosis factor ligand superfamily member 4
uIRI
unilateral ischemia–reperfusion
WB
Western blot
α-SMA
α-smooth muscle actin
TNFSF4/OX40L
AKI-CKD
GSK-3α
tubular epithelial cells
interstitial fibrosis
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