Open AccessLoss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay
Author(s) -
Fiorentino Loredana,
Cavalera Michele,
Menini Stefano,
Marchetti Valentina,
Mavilio Maria,
Fabrizi Marta,
Conserva Francesca,
Casagrande Viviana,
Menghini Rossella,
Pontrelli Paola,
Arisi Ivan,
D'Onofrio Mara,
Lauro Davide,
Khokha Rama,
Accili Domenico,
Pugliese Giuseppe,
Gesualdo Loreto,
Lauro Renato,
Federici Massimo
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201475
Subject(s) - foxo1 , diabetic nephropathy , stat1 , medicine , endocrinology , nephropathy , downregulation and upregulation , kidney , transcription factor , cancer research , diabetes mellitus , biology , gene , receptor , genetics
ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3 −/− mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3 −/− mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re‐expression of Timp3 in Timp3 −/− mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1. Studies on kidney biopsies from patients with diabetic nephropathy confirmed a significant reduction in TIMP3, FoxO1 and FoxO1 target genes involved in autophagy compared to controls, while STAT1 expression was strongly increased. Our study suggests that loss of TIMP3 is a hallmark of DKD in human and mouse models and designates TIMP3 as a new possible therapeutic target for diabetic nephropathy.