Effect of bevacizumab, a vascular endothelial growth factor inhibitor, on a rat model of peritoneal sclerosis

Costalonga

et al. 2019

Mol Med

Background Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats. Methods To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 μg/Kg, IP). Animals were followed up for 30 days. Results CG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFβ/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression. Conclusions In conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process. Electronic supplementary material The online version of this article (10.1186/s10020-019-0110-5) contains supplementary material, which is available to authorized users.

Section: Discussionmentioning

confidence: 95%

Tamoxifen and bone morphogenic protein-7 modulate fibrosis and inflammation in the peritoneal fibrosis model developed in uremic rats

Costalonga

et al. 2019

Mol Med

“…Angiogenesis is another important promoter in the progression of peritoneal fibrosis and ultrafiltration failure [ 12 , 51 ]. Peritoneal expression of VEGF is correlated with the degree of angiogenesis, and inhibition of VEGF can inhibit peritoneal angiogenesis in the rat mode of peritoneal fibrosis [ 52 – 54 ]. In the present study, we examined the effect of KX2-391 on the expression of VEGF and found that KX2-391 was effective in suppressing its expression in the peritoneum of CG injured rats.…”

Section: Discussionmentioning

confidence: 99%

Targeting Src attenuates peritoneal fibrosis and inhibits the epithelial to mesenchymal transition

Wang

et al. 2017

Oncotarget

Src has been reported to mediate tissue fibrosis in several organs, but its role in peritoneal fibrosis remains unknown. In this study, we evaluated the therapeutic effect of KX2-391, a highly selective inhibitor of Src, on the development of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, as indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts. This was accompanied by time-dependent phosphorylation of Src at tyrosine 416. Administration of KX2-391 attenuated peritoneal fibrosis and abrogated increased phosphorylation of Src and multiple signaling molecules associated with tissue fibrosis, including epidermal growth factor receptor, Akt, Signal transducer and activator of transcription 3 and nuclear factor-κB in the injured peritoneum. KX2-391 also inhibited the production of proinflammatory cytokines and the infiltration of macrophages into the injured peritoneum. In cultured human peritoneal mesothelial cells, inhibition of Src by KX2-391 or siRNA resulted in decreased expression of α-smooth muscle actin (α-SMA), fibronectin and collagen I, the hallmarks of epithelial to mesenchymal transition. These results suggest that Src is a critical mediator of peritoneal fibrosis and the epithelial to mesenchymal transition. Thus, Src could be a potential therapeutic target in the treatment of peritoneal fibrosis.

“…In an experimental peritoneal sclerosis model, bevacizumab could also reduce fibrotic process. In retinal pigment epithelial (RPE) cells, bevacizumab increased matrix metalloproteinases-2 (MMP-2) and MMP-9, but decreased VEGF-A and VEGFR-1 expression [ 43 ]. However, in human umbilical vein endothelial cells (HUVECs) in vitro , Zhang et al found that bevacizumab at clinical doses exerts pro-fibrotic effects by upregulating the expression of CTGF, bFGF, and MMP-2 [ 44 ].…”

Section: The Vascular Endothelial Growth Factor (Vegf) and Vasculamentioning

confidence: 99%

Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

Liu

Zhuang

2016

IJMS

Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs) regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs) have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis.