Effects of rikkunshito on renal fibrosis and inflammation in angiotensin II-infused mice

Kengo Azushima,Akio Yamashita,Sho Kinguchi,Sona Haku,Ryu Kobayashi,Kohji Ohki,Shintaro Minegishi,Hiromichi Wakui,Kouichi Tamura,Tomoaki Ishigami,Takahiro Yamaji,Kotaro Haruhara,Kazushi Uneda

doi:10.1038/s41598-019-42657-1

Kengo Azushima, Akio Yamashita + Show 11 more

Open Access

https://doi.org/10.1038/s41598-019-42657-1

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Abstract

The underlying pathogenesis of chronic kidney disease involves an activated renin-angiotensin system and systemic inflammation which ultimately develop renal injury. Rikkunshito (RKT) has been reported to exert anti-fibrotic and anti-inflammatory effects through enhancement of ghrelin signaling pathway. In this study, we investigated the effects of RKT on renal fibrosis and inflammation in angiotensin II (Ang II)-induced renal injury model. Ang II-infused mice exhibited hypertension, cardiac hypertrophy, increases in blood urea nitrogen and serum creatinine, moderate albuminuria and renal pathological changes such as mild urinary cast, interstitial macrophage infiltration and modest interstitial fibrosis. RKT had no evident effects on the Ang II-induced renal functional insufficiency and fibrosis, but attenuated renal interstitial macrophage infiltration. In addition, RKT significantly restored the Ang II-induced alteration in the expression of renal fibrosis- and inflammation-related genes such as type 3 collagen, transforming growth factor-β, monocyte chemoattractant protein-1 and interleukin-6. Furthermore, although RKT did not affect the expression of renal ghrelin receptor, an Ang II-induced decrease in renal sirtuin 1 expression, a critical down-stream pathway of the ghrelin receptor, was restored by RKT. These findings suggest that RKT potentially has a renal anti-inflammatory effect in the development of renal injury, and this effect could be mediated by the ghrelin signaling pathway.

Highlights

Chronic kidney disease (CKD) is clinically characterized by the decline of glomerular filtration rate and presence of albuminuria[1], in which the underlying pathogenesis involves an activated renin-angiotensin system (RAS) and systemic inflammation which develop renal injury[2]
We showed that RKT had no evident effects on angiotensin II (Ang II)-induced renal functional insufficiency and fibrosis, but attenuated renal interstitial macrophage infiltration
The Ang II-induced decrease in renal sirtuin 1 expression, a critical down-stream signaling pathway of the ghrelin receptor, was attenuated in the Ang II + RKT group. These findings suggest that RKT potentially exerts renal anti-inflammatory effects in the development of renal injury, and these effects may be mediated by the renal ghrelin signaling pathway

Summary

Introduction

Chronic kidney disease (CKD) is clinically characterized by the decline of glomerular filtration rate and presence of albuminuria[1], in which the underlying pathogenesis involves an activated renin-angiotensin system (RAS) and systemic inflammation which develop renal injury[2]. Several previous studies have reported that ghrelin replenishment therapy improves renal function and fibrosis along with the suppression of inflammation in rodent models of kidney diseases and injuries[11,12,13,14,15]. These findings suggest that, as one of agonistic agents in the ghrelin axis, RKT could exert beneficial effects against the development of kidney diseases and injuries. Of RKT on renal function and pathological changes, fibrosis- and inflammation-related gene expression and the ghrelin signaling pathway

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