Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 3, Pages 441-455Publisher
WILEY-BLACKWELL
DOI: 10.1002/emmm.201201475
Keywords
autophagy; diabetic nephropathy; FoxO1; STAT1; TIMP3
Categories
Funding
- JDRF [RRG 1-2007-665]
- Fondazione Roma Sostegno alla Ricerca Biomedica
- Telethon [GGP08065 2008]
- PRIN [2009FATXW3_002]
- FIRB [RBAP10L8TY]
- Ministero della Salute, Ricerca Finalizzata
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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.
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