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KRT20 suppresses the exosomal secretion of PRDX2 to mitigate ferroptosis in acute kidney injury

ABSTRACT: Acute kidney injury (AKI) is a commonly observed but poorly understood clinical syndrome. Keratin 20 (KRT20), a key component of intermediate filaments, is generally known as a biomarker of renal tubular injury, but its role in kidney disease remains unclear. By bioinformatics analysis and further laboratory validation, we confirmed that expression of KRT20 was highly upregulated in the renal proximal tubular cells (RPTC) during the early phase of AKI prior to the rise of KIM1 gene expression. We reported here that KRT20 was upregulated via Fosb in the kidneys of ischemia/reperfusion injury and cisplatin-nephrotoxic AKI mice. Knockout of KRT20 specifically in RPTC aggravated AKI. Mechanistically, KRT20 protected against AKI by sequestering peroxiredoxin 2 (PRDX2), an antioxidant protein, to prevent renal tubular cell ferroptosis. Specifically, KRT20 bound to PRDX2 to suppress its exosomal secretion from kidney tubular cells. We further found that ALG-2-interacting protein X (Alix) interacts with PRDX2 to mediate its exosomal secretion and KRT20 competed with Alix to interact with PRDX2 at its N terminal domain and thereby inhibiting its exosomal secretion. Finally, we showed that the expression of KRT20 and PRDX2 correlated with kidney injury and decline of renal function in AKI patients. In conclusion, KRT20 is upregulated in early AKI to protect kidney tubule cells by sequestering PRDX2 and inhibiting ferroptosis. KRT20 could be an early biomarker for AKI and a potential drug target for AKI prevention and therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE278358 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.

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KRT20 suppresses the exosomal secretion of PRDX2 to mitigate ferroptosis in acute kidney injury

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