Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.
USP11 may be a key regulator in fibroblast activation during kidney fibrosis, but its clinical relevance needs further investigation.
Where it sits
this study against the rest of the cerebrolysin corpusSummary and findings
The study investigated the role of ubiquitin-specific protease 11 (USP11) in renal interstitial fibroblasts using cultured NRK-49F cells. Uric acid increased USP11 levels by 3-4 fold, and its depletion reduced α-SMA and collagen I expressions by 70-90%. USP11 influenced fibroblast activation through epidermal growth factor receptor signaling pathways.
Abstract
Chronic kidney disease is a worldwide health problem, and its incidence is on the rise. It has previously been shown that ubiquitin-specific protease 11 (USP11) promotes partial epithelial-to-mesenchymal transition in uric acid-stimulated tubular epithelial cells during renal fibrosis. However, its specific function and mechanism in renal interstitial fibroblasts is still unknown. In this study, we found that uric acid could also upregulate the USP11 levels in cultured fibroblasts (NRK-49F) under dose gradient and time gradient, with an approximately 3-4 fold increase. Genetic and pharmacological depletion of USP11 blocked activation of renal interstitial fibroblasts leading to an approximately 70-90% reduction in α-SMA and collagen I expressions. USP11 increased the phosphorylation level of epidermal growth factor receptor, thereby activating its downstream signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/protein kinase B and mitogen-activated protein kinase /extracellular regulated protein kinases, which further activated nuclear transcription factors, Snail and Slug. Moreover, USP11 could also affect the proliferation and migration of NRK49F, by upregulating the expression levels of proliferating cell nuclear antigen and cyclin E. Thus, our study offers comprehensive evidence that USP11 is a promising target for kidney fibrosis and that inhibiting USP11 could be an effective strategy for treating chronic kideny disease.
Background
Chronic kidney disease (CKD) is a significant global health issue with increasing incidence. Previous research has identified ubiquitin-specific protease 11 (USP11) as a promoter of partial epithelial-to-mesenchymal transition in renal fibrosis. This study explores the specific role and mechanism of USP11 in renal interstitial fibroblasts, which are crucial in the progression of kidney fibrosis.
Methods
The study utilized cultured NRK-49F renal interstitial fibroblasts to examine the effects of uric acid on USP11 levels. Genetic and pharmacological methods were employed to deplete USP11 and assess its impact on fibroblast activation. The study measured changes in protein expressions and signaling pathways to determine the role of USP11.
Results
Uric acid exposure resulted in a 3-4 fold increase in USP11 levels in fibroblasts. Depletion of USP11 led to a 70-90% reduction in α-SMA and collagen I expressions, indicating reduced fibroblast activation. USP11 was found to enhance phosphorylation of the epidermal growth factor receptor, activating downstream signaling pathways such as PI3K/protein kinase B and MAPK/ERK, which further influenced nuclear transcription factors Snail and Slug.
Interpretation
The findings suggest that USP11 plays a significant role in the activation and proliferation of renal interstitial fibroblasts through specific signaling pathways. While the study provides mechanistic insights, the clinical significance remains uncertain due to the in vitro nature of the research. Further studies are needed to evaluate the potential of USP11 as a therapeutic target in human CKD.
Key findings
- 3-4 fold increase in USP11 levels in fibroblasts with uric acid.
- 70-90% reduction in α-SMA and collagen I expressions with USP11 depletion.
- USP11 increased phosphorylation of epidermal growth factor receptor.
- Activation of PI3K/protein kinase B and MAPK/ERK pathways by USP11.
- Upregulation of proliferating cell nuclear antigen and cyclin E by USP11.
Limitations
- in vitro only, no human data
- single cell line model
- mechanistic focus, not clinical outcomes