title: Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay.
abstract: 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.
authors: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors: Loredana
authors: L
authors: Fiorentino
authors: Michele
authors: M
authors: Cavalera
authors: Stefano
authors: S
authors: Menini
authors: Valentina
authors: V
authors: Marchetti
authors: Maria
authors: M
authors: Mavilio
authors: Marta
authors: M
authors: Fabrizi
authors: Francesca
authors: F
authors: Conserva
authors: Viviana
authors: V
authors: Casagrande
authors: Rossella
authors: R
authors: Menghini
authors: Paola
authors: P
authors: Pontrelli
authors: Ivan
authors: I
authors: Arisi
authors: Mara
authors: M
authors: D'Onofrio
authors: Davide
authors: D
authors: Lauro
authors: Rama
authors: R
authors: Khokha
authors: Domenico
authors: D
authors: Accili
authors: Giuseppe
authors: G
authors: Pugliese
authors: Loreto
authors: L
authors: Gesualdo
authors: Renato
authors: R
authors: Lauro
authors: Massimo
authors: M
authors: Federici
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001706:Biopsy; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency* / Q000235:genetics; D014162:Transfection
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3
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