Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. Issue 3 (12th February 2013)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 5:Issue 3(2013:Mar.)
• Page Start: 441
• Page End: 455
• Publication Date: 2013-02-12
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201201475
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic <italic>Timp3</italic>^{<italic>−/−</italic>} mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of <italic>Foxo1</italic> expression in diabetic <italic>Timp3</italic>^{<italic>−/−</italic>} 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 <italic>Timp3</italic>^{<italic>−/−</italic>} 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 <italic>Timp3</italic> 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.</p> <p>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.</p> </abstract>