Korean J Intern Med.  2016 Mar;31(2):323-334. 10.3904/kjim.2015.004.

Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice

• Chung S
• Jeong JY
• Chang YK
• Choi DE
• Na KR
• Lim BJ
• Lee KW

• KMID: 2373808
• DOI: http://doi.org/10.3904/kjim.2015.004

Abstract

BACKGROUND/AIMS
There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2.
METHODS
We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed.
RESULTS
Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys.
CONCLUSIONS
TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

Keyword

Toll-like receptor 2; Renin-angiotensin system; Unilateral ureteral obstruction

MeSH Terms

Amides/*pharmacology
Angiotensin II/pharmacology
Animals
Disease Models, Animal
Fibrosis
Fumarates/*pharmacology
Kidney/*drug effects/metabolism/pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Nephritis, Interstitial/genetics/metabolism/pathology/*prevention & control
RNA, Messenger/genetics/metabolism
Renin/*antagonists & inhibitors/metabolism
Renin-Angiotensin System/*drug effects
Toll-Like Receptor 2/deficiency/drug effects/genetics/*metabolism
Ureteral Obstruction/*drug therapy/genetics/metabolism/pathology
Amides
Angiotensin II
Fumarates
RNA, Messenger
Renin
Toll-Like Receptor 2