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Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney

Nicholas A Maksimowski1, Xuewen Song2, Eun Hui Bae3

  • 1Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.

International Journal of Molecular Sciences
|September 10, 2021
PubMed

Insights

Follistatin-like-1 (FSTL1) is a key factor in chronic kidney disease (CKD) progression. This study links FSTL1 to kidney damage and disease advancement in both mouse models and human patients.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Chronic kidney disease (CKD) progression mechanisms remain incompletely understood.
  • Follistatin-like-1 (FSTL1) was identified as a significantly overexpressed gene in a mouse model of progressive nephropathy.
  • FSTL1 receptors (Tlr4, Dip2a) were upregulated in kidney injury models.

Purpose of the Study:

  • To investigate the role of Follistatin-like-1 (FSTL1) in the progression of chronic kidney disease (CKD).
  • To determine the cellular localization and functional impact of FSTL1 in kidney cells.
  • To assess the association of FSTL1 with clinical parameters and disease progression in human kidney diseases.

Main Methods:

  • Microarray analysis in *Col4a3* mice and unilateral ureteral obstruction (UUO) models.
  • RNAscope in situ hybridization and in silico analysis of human kidney single-cell transcriptomics.
  • In vitro studies using cultured kidney cells to assess FSTL1 signaling pathways and gene expression.
  • Analysis of the NEPTUNE cohort for correlations between FSTL1 levels and clinical outcomes in FSGS, MN, and IgAN.

Main Results:

  • FSTL1 was significantly overexpressed early in a mouse model of progressive kidney disease.
  • FSTL1 was localized to interstitial fibroblasts/myofibroblasts in mouse and human kidneys.
  • In vitro, FSTL1 activated AP1 and NFκB, increased collagen and IL6 expression, and induced apoptosis.
  • In human patients, FSTL1 expression correlated with age, eGFR, proteinuria, and interstitial fibrosis.
  • High baseline FSTL1 levels were associated with greater clinical CKD progression.

Conclusions:

  • Follistatin-like-1 (FSTL1) is a fibroblast-derived cytokine implicated in experimental and clinical CKD progression.
  • FSTL1 signaling pathways contribute to kidney fibrosis and inflammation.
  • FSTL1 serves as a potential biomarker and therapeutic target for managing CKD progression.
Keywords:
FSTL1apoptosiscytokinesfibrosisinflammationkidneynephrotic syndrome

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