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2018 ; 8
(1
): 8319
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Blockade of HMGB1 Attenuates Diabetic Nephropathy in Mice
#MMPMID29844451
Chen X
; Ma J
; Kwan T
; Stribos EGD
; Messchendorp AL
; Loh YW
; Wang X
; Paul M
; Cunningham EC
; Habib M
; Alexander IE
; Sharland AF
; Chadban SJ
; Wu H
Sci Rep
2018[May]; 8
(1
): 8319
PMID29844451
show ga
Activation of TLR2 or TLR4 by endogenous ligands such as high mobility group box
1 (HMGB1) may mediate inflammation causing diabetic kidney injury. We determined
whether blockade of HMGB1 signaling by: (1) supra-physiological production of
endogenous secretory Receptor for Advanced Glycation End-products (esRAGE), a
receptor for HMGB1; (2) administration of HMGB1 A Box, a specific competitive
antagonist, would inhibit development of streptozotocin induced diabetic
nephropathy (DN). Wild-type diabetic mice developed albuminuria, glomerular
injuries, interstitial fibrosis and renal inflammation. Using an adeno-associated
virus vector, systemic over-expression of esRAGE afforded significant protection
from all parameters. No protection was achieved by a control vector which
expressed human serum albumin. Administration of A Box was similarly protective
against development of DN. To determine the mechanism(s) of protection, we found
that whilst deficiency of TLR2, TLR4 or RAGE afforded partial protection from
development of DN, over-expression of esRAGE provided additional protection in
TLR2(-/-), modest protection against podocyte damage only in TLR4(-/-) and no
protection in RAGE(-/-) diabetic mice, suggesting the protection provided by
esRAGE was primarily through interruption of RAGE and TLR4 pathways. We conclude
that strategies to block the interaction between HMGB1 and its receptors may be
effective in preventing the development of DN.
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