Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay

L Fiorentino, M Cavalera, S Menini… - EMBO molecular …, 2013 - embopress.org
L Fiorentino, M Cavalera, S Menini, V Marchetti, M Mavilio, M Fabrizi, F Conserva…
EMBO molecular medicine, 2013embopress.org
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 …
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.
embopress.org