Abstract
Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury, whereas it is expanded to interstitial cells in fibrosis in mice and humans. Foxd1-mediated deletion of Stat3 protects mice from folic-acid- and aristolochic-acid-induced kidney fibrosis. Mechanistically, STAT3 upregulates the inflammation and differentiates pericytes into myofibroblasts. STAT3 activation increases migration and profibrotic signaling in genome-edited, pericyte-like cells. Conversely, blocking Stat3 inhibits detachment, migration, and profibrotic signaling. Furthermore, STAT3 binds to the Collagen1a1 promoter in mouse kidneys and cells. Together, our study identifies a previously unknown function of STAT3 that promotes kidney fibrosis and has therapeutic value in fibrosis.
Highlights
Diverse cell types play crucial functions in the cellular processes of tissue fibrosis (Quan et al, 2006; Willis et al, 2006; Wynn, 2007; Zeisberg et al, 2007), including kidney fibrosis (OhAinmhire and Humphreys, 2017; El Agha et al, 2017; Kramann et al, 2015b; Mack and Yanagita, 2015)
We found that interleukin-6 (IL-6) mediates Signal transduction and activator of transcription 3 (STAT3) phosphorylation in human proximal tubular epithelial cells in acute kidney injury (AKI) (Ajay et al, 2014a) and IL-6-mediated STAT3 activation is observed in fibroblasts in vitro (Craciun et al, 2014)
STAT3 expression is increased in AKI and CKD in human and mouse kidneys We obtained human kidney specimens from the Brigham and Women’s Hospital pathology core from healthy individuals, those with acute tubular necrosis (ATN) representing AKI and diabetic nephropathy (DN) representing chronic kidney disease (CKD)
Summary
Diverse cell types play crucial functions in the cellular processes of tissue fibrosis (Quan et al, 2006; Willis et al, 2006; Wynn, 2007; Zeisberg et al, 2007), including kidney fibrosis (OhAinmhire and Humphreys, 2017; El Agha et al, 2017; Kramann et al, 2015b; Mack and Yanagita, 2015). Signal transduction and activator of transcription 3 (STAT3) is phosphorylated in multiple cell types, including fibroblasts, immune cells, and epithelial cells, in response to growth factors and inflammatory response (Leu et al, 2003; Okamoto et al, 1997). Transforming growth factor b (TGF-b)-dependent STAT3 activation (Zehender et al, 2018) increases the profibrotic signaling in fibroblasts in systemic sclerosis (Chakraborty et al, 2017). Depending on the type of growth factor and cellular machinery, STAT3 initiates specific transcriptional programs in the cells (Kasembeli et al, 2018; Shain et al, 2009; Yu et al, 2009). Genetic depletion of STAT3 from tubular epithelial cells protects mice from nephrectomy-induced kidney fibrosis by inhibiting tubulointerstitial crosstalk (Bienaime et al, 2016). STAT3 deletion from podocytes protects mice from HIV-1-associated nephropathy
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