Cyclic helix B peptide inhibits ischemia reperfusion-induced renal fibrosis via the PI3K/Akt/FoxO3a pathway

Abstract

Renal fibrosis is a main cause of end-stage renal disease. Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function. We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. In this study, we evaluated the effect of CHBP on renal fibrosis in an in vivo ischemia reperfusion injury (IRI) model and in vitro TGF-β-stimulated tubular epithelial cells (TCMK-1 and HK-2) model. In the IRI in vivo model, mice were randomly divided into sham (sham operation), IR and IR + CHBP groups (n = 6). CHBP (8 nmol/kg) was administered intraperitoneally at the onset of reperfusion, and renal fibrosis was evaluated at 12 weeks post-reperfusion. Our results showed that CHBP markedly attenuated the IRI-induced deposition of collagen I and vimentin. In the in vitro model, CHBP reversed the TGF-β-induced down-regulation of E-cadherin and up-regulation of α-SMA and vimentin. Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA. These findings demonstrate that CHBP attenuates renal fibrosis and the epithelial-mesenchymal transition of tubular cells, possibly through suppression of the PI3K/Akt pathway and thereby the inhibition FoxO3a activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0699-2) contains supplementary material, which is available to authorized users.

Potent Therapy and Transcriptional Profile of Combined Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA against Kidney Ischemia/Reperfusion Injury in mice

“…The present study demonstrated that a single dose of CHBP, plasma half-life 300 min, (Yang et al, 2014b) administrated 15 min after reperfusion greatly ameliorated renal IR injury at the early stage of 48 h. This result was consistent with the evidence that a single dose of CHBP protected the kidney from IR injury at 12-week (Yang et al, 2015c). Linear HBSP, plasma half-life about 2 min, administered at 1 h, 6 h and 12 h protected the kidney against IR injury at 24 h (Brines et al, 2008).…”

“…In the IR kidney, CHBP reduces endoplasmic reticulum stress and increases autophagy (Yang et al, 2014b), leading to less apoptosis (Kaushal and Shah 2016). CHBP also ameliorated renal in ammation and reduced chronic deposition of extracellular matrix through inactivating forkhead box O 3a (FoxO3a) after IR (Yang et al, 2015c). Nevertheless, the exact underling mechanism in the renoprotection of CHBP is incompletely understood.…”

Advances in Understanding the Effects of Erythropoietin on Renal Fibrosis

“…Increased Akt signaling is associated with suppression of cell apoptosis and promotion of renal fibrosis in IR injuryinduced acute kidney injury (84). However, suppression of Akt phosphorylation accelerates tubular repair and inhibits renal fibrosis (85).…”

Curcumin alleviates ischemia reperfusion‐induced late kidney fibrosis through the APPL1/Akt signaling pathway

“…Ischemia reperfusion (IR)‐induced AKI is common in clinical practice, can lead to renal fibrosis, and is an important risk factor for chronic kidney disease (CKD). Although a large amount of evidence has confirmed the progression from IR‐induced AKI to subsequent kidney fibrosis (Kim & Padanilam, ; Yang et al, ), the molecular mechanism of AKI‐induced renal fibrosis has yet to be understood. Thus, identifying effective drug treatments for this disorder has important clinical significance.…”