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MicroRNA-23b Targets Ras GTPase-Activating Protein SH3 Domain-Binding Protein 2
to Alleviate Fibrosis and Albuminuria in Diabetic Nephropathy
#MMPMID26839366
Zhao B
; Li H
; Liu J
; Han P
; Zhang C
; Bai H
; Yuan X
; Wang X
; Li L
; Ma H
; Jin X
; Chu Y
J Am Soc Nephrol
2016[Sep]; 27
(9
): 2597-608
PMID26839366
show ga
Diabetic nephropathy (DN) is a frequent and severe complication of diabetes that
is structurally characterized by glomerular basement membrane thickening,
extracellular matrix accumulation, and destabilization of podocyte foot
processes. MicroRNAs (miRNAs) are dysregulated in DN, but identification of the
specific miRs involved remains incomplete. Here, we confirm that the peripheral
blood from patients with diabetes and the kidneys of animals with type 1 or 2
diabetes have low levels of miR-23b compared with those of their nondiabetic
counterparts. Furthermore, exposure to high glucose downregulated miR-23b in
cultured kidney cells. In contrast, renal expression of Ras GTPase-activating
protein SH3 domain-binding protein 2 (G3BP2), a putative miR-23b target,
increased in DN. In vitro, overexpression of miR-23b decreased, and inhibition of
miR-23b increased, G3BP2 expression levels. Bioinformatics analysis also revealed
p53 binding sites in the miR-23b promoter; in vitro inhibition of p53 or the
upstream p38 mitogen-activated protein kinase (p38MAPK) upregulated miR-23b
expression in high-glucose conditions. In turn, inhibition of G3BP2 or
overexpression of miR-23b downregulated p53 and p38MAPK expression in
high-glucose conditions. In vivo, overexpression of miR-23b or inhibition of p53
in db/db mice reversed hyperalbuminuria and kidney fibrosis, whereas miR-23b
antagomir treatment promoted renal fibrosis and increased albuminuria in
wild-type mice. These data suggest that hyperglycemia regulates pathogenic
processes in DN through an miR-23b/G3BP2 feedback circuit involving p38MAPK and
p53. In conclusion, these results reveal a role for miR-23b in DN and indicate a
novel potential therapeutic target.
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