Smad2-dependent downregulation of miR-30 is required for TGF-ß-induced apoptosis
in podocytes.
Authors Shi S, Yu L, Zhang T, Qi H, Xavier S, Ju W, Bottinger E
Submitted By Erwin Bottinger on 2/7/2014
Status Published
Journal PLoS ONE
Year 2013
Date Published
Volume : Pages 8 : e75572
PubMed Reference 24086574
Abstract Transforming growth factors beta (TGF-ß) are multi-functional cytokines capable
of inducing apoptosis in epithelial cells, including glomerular podocytes. We
and others have previously shown that podocyte-selective genetic deletion of the
microRNA (miR)-processing enzyme, Dicer, caused glomerulosclerosis that was
associated with podocyte apoptosis, and the miR-30 family was implicated in the
process. Here, we report that apoptosis-associated genes were highly enriched
among the predicted targets of miR-30 when compared with randomly selected miRs
(26% vs. 4.5 ± 2.1%) or with the known TGF-ß-regulated miR-192 (6%), miR-216a
(5.1%), and miR-217 (0%). miR-30 family members were abundantly expressed in
podocytes in normal mice but were downregulated in albumin/TGF-ß transgenic mice
with podocyte apoptosis and glomerulosclerosis. In vitro, TGF-ß downregulated
miR-30s in wildtype and Smad3-deficient, but not Smad2- or
Smad2/Smad3-deficient, podocytes. The TGF-ß-induced activation of caspase 3 and
an increase in TUNEL-positive nuclei were significantly inhibited by the
lentivirus-mediated overexpression of miR-30d, but not by a scrambled control
miR, in podocytes. TGF-ß stimulated the phosphorylation of pro-apoptotic p53 in
podocytes with lentiviral expression of a scrambled miR, but not in podocytes
expressing miR-30d. In contrast, miR-30d had no effect on the phosphorylation of
pro-apoptotic p38 MAP kinase induced by TGF-ß. Thus, we report that
Smad2-dependent inhibition of miR-30s in podocytes is required for the
activation of p53 and the induction of apoptosis by TGF-ß. These results
demonstrate a novel functional role for miR-30 in podocyte survival and indicate
that the loss of miR-30 survival signaling is a novel and specific mechanism of
TGF-ß-induced podocyte apoptosis during glomerulosclerosis. We propose the
therapeutic replacement of miR-30 as a novel strategy to prevent the podocyte
apoptosis that is characteristic of progressive glomerular diseases.

Investigators with authorship
Erwin BottingerMount Sinai School of Medicine