A blockade of PI3K\u03b3 signaling effectively mitigates angiotensin II-induced renal injury and fibrosis in a mouse model

Xinyi Yu,Liqun Chen,Ruyi Zhang,Tong‐Chuan He ,Wei Luo ,Zongyue Zeng,Hue H Luu,Shifeng Huang,Chen Zhao,Bo Huang,Yi Shu,Yixiao Feng,Rex C Haydon,Lijiang Zeng ,Wei Liu,Yunlong Xia ,Chengfu Yuan,Jiayan Lei,Linghuan Zhang,Hongmei Zhang,Bo Zhang,Xi Wang,Shujuan Yan,Xi Zhang,Hua Gan

doi:10.1038/s41598-018-29417-3

Abstract

Chronic kidney disease (CKD) poses a formidable challenge for public healthcare worldwide as vast majority of patients with CKD are also at risk of accelerated cardiovascular disease and death. Renal fibrosis is the common manifestation of CKD that usually leads to end-stage renal disease although the molecular events leading to chronic renal fibrosis and eventually chronic renal failure remain to be fully understood. Nonetheless, emerging evidence suggests that an aberrant activation of PI3Kγ signaling may play an important role in regulating profibrotic phenotypes. Here, we investigate whether a blockade of PI3Kγ signaling exerts any beneficial effect on alleviating kidney injury and renal fibrosis. Using a mouse model of angiotensin II (Ang II)-induced renal damage, we demonstrate that PI3Kγ inhibitor AS605240 effectively mitigates Ang II-induced increases in serum creatinine and blood urea nitrogen, renal interstitial collagen deposition, the accumulation of ECM proteins and the expression of α-Sma and fibrosis-related genes in vivo. Mechanistically, we reveal that AS605240 effectively inhibits Ang II-induced cell proliferation and phosphorylation of Akt in fibroblast cells. Furthermore, we demonstrate that Ang II-upregulated expression of IL-6, Tnf-α, IL-1β and Tgf-β1 is significantly attenuated in the mice treated with AS605240. Taken together, our results demonstrate that PI3Kγ may function as a critical mediator of Ang II-induced renal injury and fibrosis. It is thus conceivable that targeted inhibition of PI3Kγ signaling may constitute a novel therapeutic approach to the clinical management of renal fibrosis, renal hypertension and/or CKD.

Highlights

Chronic kidney disease (CKD) is a group for heterogeneous disorders affecting kidney structure and function presenting as a growing public health problem worldwide[1,2,3]
While the total Akt protein levels were similar among the three groups, the phosphorylated Akt (p-Akt) level was significantly increased in angiotensin II (Ang II)-stimulated cells, which was effectively blocked by PI3Kγ inhibitor AS605240 (Fig. 6A)
We found that the expression of interleukin-6 (IL-6), tumor necrosis factor-α (Tnf-α), interleukin-1β (IL-1β), and transforming growth factor-β1 (Tgf-β1) was upregulated significantly in the mice treated with Ang II (p < 0.01) (Fig. 7)

Summary

Introduction

Chronic kidney disease (CKD) is a group for heterogeneous disorders affecting kidney structure and function presenting as a growing public health problem worldwide[1,2,3]. Tubulointerstitial fibrosis is characterized by fibroblast activation and excessive production and deposition of extracellular matrix (ECM), resulting in the destruction of renal parenchyma and causes progressive loss of kidney function[16,18,19,20]. There is an unmet clinical challenge to fully understand the cellular and molecular mechanisms underlying the pathogenesis of CKD21 It has been well-recognized that activation of the renin–angiotensin system (RAS) plays a central role in initiation and progression of CKD through regulation of inflammation and fibrosis[22,23]. It was shown that mice lacking PI3Kγ were protected from hypertension induced by Ang II27, and resistant to bleomycin-induced pulmonary injury, angiogenesis and fibrosis[28] These studies strongly suggest that an aberrant activation of PI3Kγ signaling may play an essential role in regulating profibrotic phenotypes. It is conceivable that targeted inhibition of PI3Kγ signaling may be explored as a novel therapeutic approach to the clinical management of renal fibrosis, renal hypertension and/or CKD

Methods

Results

Conclusion