Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration
Amrendra K. Ajay,
Li Zhao,
Shruti Vig,
Mai Fujiwara,
Sudhir Thakurela,
Shreyas Jadhav,
Andrew Cho,
I-Jen Chiu,
Yan Ding,
Krithika Ramachandran,
Arushi Mithal,
Aanal Bhatt,
Pratyusha Chaluvadi,
Manoj K. Gupta,
Sujal I. Shah,
Venkata S. Sabbisetti,
Ana Maria Waaga-Gasser,
David A. Frank,
Gopal Murugaiyan,
Joseph V. Bonventre,
Li-Li Hsiao
Affiliations
Amrendra K. Ajay
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Li Zhao
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Renal Medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
Shruti Vig
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Mai Fujiwara
Ann Romney Centre for Neurological Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Sudhir Thakurela
Broad Institute of MIT and Harvard, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Shreyas Jadhav
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Andrew Cho
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
I-Jen Chiu
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Yan Ding
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Krithika Ramachandran
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Arushi Mithal
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Aanal Bhatt
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Pratyusha Chaluvadi
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Manoj K. Gupta
Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
Sujal I. Shah
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Venkata S. Sabbisetti
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Ana Maria Waaga-Gasser
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
David A. Frank
Department of Medical Oncology, Dana Farber Cancer Research Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Gopal Murugaiyan
Ann Romney Centre for Neurological Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Joseph V. Bonventre
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Li-Li Hsiao
Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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.
