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Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis
Shihui Xu1, Xiaobing Yang1, Qingzhou Chen1
1Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Background:
The role of the IL6 family members in organ fibrosis, including renal interstitial fibrosis (TIF), has been widely explored. However, few studies have ever simultaneously examined them in the same cohort of patients. Besides, the role of leukemia inhibitory factor (LIF) in TIF remains unclear.
Methods:
RNA-seq data of kidney biopsies from chronic kidney disease (CKD) patients, in both public databases and our assays, were used to analyze transcript levels of IL6 family members. Two TIF mouse models, the unilateral ureteral obstruction (UUO) and the ischemia reperfusion injury (IRI), were employed to validate the finding. To assess the role of LIF in vivo, short hairpin RNA, lenti-GFP-LIF was used to knockdown LIF receptor (LIFR), overexpress LIF, respectively. LIF-neutralizing antibody was used in therapeutic studies. Whether urinary LIF could be used as a promising predictor for CKD progression was investigated in a prospective observation patient cohort.
Findings:
Among IL6 family members, LIF is the most upregulated one in both human and mouse renal fibrotic lesions. The mRNA level of LIF negatively correlated with eGFR with the strongest correlation and the smallest P value. Baseline urinary concentrations of LIF in CKD patients predict the risk of CKD progression to end-stage kidney disease by Kaplan-Meier analysis. In mouse TIF models, knockdown of LIFR alleviated TIF; conversely, overexpressing LIF exacerbated TIF. Most encouragingly, visible efficacy against TIF was observed by administering LIF-neutralizing antibodies to mice. Mechanistically, LIF-LIFR-EGR1 axis and Sonic Hedgehog signaling formed a vicious cycle between fibroblasts and proximal tubular cells to augment LIF expression and promote the pro-fibrotic response via ERK and STAT3 activation.
Interpretation:
This study discovered that LIF is a noninvasive biomarker for the progression of CKD and a potential therapeutic target of TIF.
Fundings:
Stated in the Acknowledgements section of the manuscript.
Insights
Leukemia inhibitory factor (LIF) is a key driver of kidney fibrosis and a promising biomarker for chronic kidney disease (CKD) progression. Targeting LIF offers a potential therapeutic strategy for treating fibrotic kidney disease.
Area of Science:
- Nephrology
- Fibrosis Research
- Biomarker Discovery
Background:
- The IL-6 family's role in organ fibrosis is known, but simultaneous examination in patients is limited.
- The specific role of leukemia inhibitory factor (LIF) in tubulointerstitial fibrosis (TIF) remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of IL-6 family members, particularly LIF, in renal interstitial fibrosis (TIF).
- To determine if urinary LIF can serve as a predictive biomarker for chronic kidney disease (CKD) progression.
- To explore LIF as a potential therapeutic target for TIF.
Main Methods:
- Analyzed RNA-seq data from human CKD kidney biopsies and mouse TIF models (UUO, IRI).
- Utilized in vivo knockdown/overexpression of LIF receptor (LIFR) and LIF in mouse models.
- Administered LIF-neutralizing antibodies for therapeutic assessment.
- Correlated urinary LIF levels with CKD progression in a prospective patient cohort.
Main Results:
- LIF was the most upregulated IL-6 family member in human and mouse fibrotic kidney lesions.
- Urinary LIF levels strongly correlated with decreased eGFR and predicted CKD progression.
- LIF manipulation in mice directly impacted TIF severity; LIF-neutralizing antibodies showed efficacy.
- Identified the LIF-LIFR-EGR1 axis and Sonic Hedgehog signaling as key mechanistic pathways.
Conclusions:
- Leukemia inhibitory factor (LIF) is a significant contributor to TIF.
- Urinary LIF is a noninvasive biomarker for predicting CKD progression.
- LIF presents a viable therapeutic target for treating TIF.
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