Signalling pathways involved in hypoxia-induced renal fibrosis

Abstract

Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease (CKD) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end-stage kidney disease (ESKD), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia-induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia-inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia-induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF, TGF-β, Notch, PKC/ERK, PI3K/Akt, NF-κB, Ang II/ROS and microRNAs. Roles of molecules such as IL-6, IL-18, KIM-1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia-responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD.

Keywords: Signalling pathways; hypoxia; renal fibrosis.

Figure 1

A schematic of tubulointerstitial fibrosis mediated by hypoxia‐inducible signalling pathways. (A) Under hypoxia condition, HIF signalling promotes renal fibrogenesis by activation of inflammatory responses, ECM, and up‐regulation of expression of EMT regulators to enhance tubular EMT, such as Twist, Bmi1, LOXs. (B) Additionally, other signalling pathways mediated by TGF‐β, Notch, PKC/ERK, PI3K/Akt, NF‐κB, Ang II/ROS, ADO, microRNAs, IL‐6, IL‐18, KIM‐1 and their downstream signals are also involved in hypoxia‐induced renal fibrosis, through their specific roles, respectively. EMT, epithelial‐to‐mesenchymal transition; ECM, extracellular matrix; Mfs, myofibroblasts;PAI, plasminogen activator inhibitor 1; ET‐1, endothelin‐1; CTGF, connective tissue growth factor; TIMP1, tissue inhibitor of metalloproteinase 1; TNF‐1α, tumour necrosis factor‐1α; PDGF, platelet‐derived growth factor; IL‐6, interleukin‐6; FGF, fibroblast growth factor‐2; MCP‐1, monocyte chemotactic protein‐1.

Figure 2

An Overview of signalling pathways(A) and their interactions(B) involved in hypoxia‐induced renal fibrosis. All these signals act at various levels in concert to amplify the pathogenesis of fibrogenic response and CKD progression. HIF, hypoxia‐inducible factor; LOXs, lysyl oxidases; CTGF, connective tissue growth factor; Egr‐1, early growth response‐1; BVR, biliverdin reductase; URG11, up‐regulated gene 11; KIM‐1, kidney injury molecule‐1; BVR, Biliverdin reductase; ADO, adenosine; IL‐6, interleukin‐6; ROS, reactive oxygen species; TGF‐β, transforming growth factor‐β; Ang II, Angiotensin II; mTOR, mammalian target of rapamycin; PHD, prolyl hydroxylase domain protein; CEBPD, CCAAT/enhancer‐binding protein δ.