Journal
KIDNEY INTERNATIONAL
Volume 103, Issue 3, Pages 544-564Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.11.027
Keywords
epidermal growth factor receptor; G2/M arrest; kidney fibrosis; partial epithelial-mesenchymal transition; ubiquitin-specific protease
Categories
Funding
- National Nature Science Foundation of China [82070791, 81670690, 81470991, 81200492, 82070700, 81830021]
- Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai [PWR12021-02]
- Shanghai Scienti fic Committee of China [20ZR1445800, 13PJ1406900]
- Shanghai Health Bureau and Shanghai Administration of Traditional Chinese Medicine of China [ZHYY- ZXYJHZX-202114]
- Project of Pudong Health Bureau of Shanghai [PW2021D-04, PWZxk2017-05]
- Branch Grant of National Key R&D Program of China [2018YFA0108802]
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This study found that the aberrant expression of USP11 is related to tumor progression in kidney fibrosis. Inhibition of USP11 can attenuate pathological lesions and improve kidney function, suggesting its potential as a therapeutic strategy for patients with chronic kidney disease.
The aberrant expression of ubiquitin-specific protease 11 (USP11) is believed to be related to tumor progression. However, few studies have reported the biological function and clinical importance of USP11 in kidney fibrosis. Here, we demonstrated USP11 was highly upregulated in the kidneys from patients with chronic kidney disease and correlated positively with fibrotic lesion but negatively with kidney function. Conditional USP11 deletion or pharmacologic inhibition with Mitoxantrone attenuated pathological lesions and improved kidney function in both hyperuricemic nephropathy (HN)- and folic acid (FA)-induced mouse models of kidney fibrosis. Mechanistically, by RNA sequencing, USP11 was found to be involved in nuclear gene transcription of the epidermal growth factor receptor (EGFR). USP11 co-immunoprecipitated and co-stained with extra-nuclear EGFR and deubiquitinated and protected EGFR from proteasome-dependent degradation. Genetic or pharmacological depletion of USP11 facilitated EGFR degradation and abated augmentation of TGF-beta 1 and downstream signaling. This consequently alleviated the partial epithelial-mesenchymal transition, G2/M arrest and aberrant secretome of profibrogenic and proinflammatory factors in uric acid-stimulated tubular epithelial cells. Moreover, USP11 deletion had anti-fibrotic and anti-inflammatory kidney effects in the murine HN and FA models. Thus, our study provides evidence supporting and that inhibition of USP11 has potential to be an effective strategy for patients with chronic kidney disease.
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