Netrin-1 attenuates the progression of renal dysfunction by blocking endothelial-to-mesenchymal transition in the 5/6 nephrectomy rat model

Bai, Jiuxu; Hao, Junfeng; Xiao-ling, Zhang; Cui, Hanmin; Han, Jingming; Cao, Ning

doi:10.1186/s12882-016-0260-4

Cited by 19 publications

(13 citation statements)

References 30 publications

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“…Here, we observed that CKD was associated with a decrease in glomerular endothelial cell and podocyte density as reported previously (Sup Fig. 5A,B) 44,45 . miR299a-5p inhibition significantly preserved podocytes (Sup Fig.…”

Section: Tgfβ1-dependent Repression Of Fst Is Mediated By Mir299a-5psupporting

confidence: 89%

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin

Mehta

Zhang

et al. 2021

Sci Rep

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Caveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3′UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFβ1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFβ1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFβ1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD.

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Section: Tgfβ1-dependent Repression Of Fst Is Mediated By Mir299a-5psupporting

confidence: 89%

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin

Mehta

Zhang

et al. 2021

Sci Rep

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“…Renal interstitial fibrosis (RIF) is a final common pathway for progression of all the various chronic kidney diseases (CKD) to end-stage renal disease (ESRD), causing the need of continuous renal replacement therapy in form of dialysis or transplantation (1). The main features of RIF, including renal tubular atrophy/dilatation, interstitial inflammatory cell infiltration, induction of apoptosis, fibroblasts activation and extracellular matrix (ECM) deposition, have been previously described (2).…”

Section: Introductionmentioning

confidence: 99%

Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

Wang

et al. 2020

Exp Ther Med

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Renal interstitial fibrosis (RIF) is a common pathological process that accompanies chronic kidney disease (CKD) and that progresses to end-stage renal failure (ESRD). Accumulating evidence has revealed that persistent mammalian target of rapamycin (mTOR) activation in kidneys is closely associated with the occurrence and progression of CKD. The DEP domain-containing mTOR interacting protein (Deptor) is an endogenous negative regulator of mTOR. Metformin can attenuate renal fibrosis in an animal model of diabetic nephropathy. Previous studies demonstrated that metformin can attenuate renal fibrosis in several models of CKD. However, the precise mechanisms of this effect are not well understood. The present study aimed to examine the mechanism of action of metformin on unilateral ureteral obstruction (UUO)-induced RIF in rats in vivo. Sprague-Dawley rats were randomly divided into a sham-operated group, three UUO groups examined at different time points (3, 7 and 14 days after UUO surgery), and three metformin-treated groups, treated with three different concentrations of metformin. The metformin-treated groups were administered metformin orally every day for 14 consecutive days following surgery. The protein expression levels of Deptor, α-smooth muscle actin (α-SMA), phosphorylated (p-)mTOR, p-ribosomal protein S6 kinase (p-p70S6K) and CD68 were assessed. The present results suggested that, following UUO, there was a significant reduction of Deptor expression, and an increase in collagen deposition in the extracellular matrix over time, accompanied by an increased expression of several proteins including CD68, α-SMA, p-mTOR and p-p70S6K. Notably, metformin treatment reversed these effects. In conclusion, the present results suggested that metformin attenuated RIF of UUO rats, and the mechanism of action was found to be associated with the increase in Deptor expression and inhibition of the mTOR/p70S6K pathway in the kidneys of UUO rats.

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“…Other signaling cascades and factors that abrogate EndMT include: (i) activation of the Src signaling pathway by hydrogen sulfide during endoplasmic reticulum (ER) stress [76]; (ii) glucagon-like peptide-1 (GLP-1) suppression of hyperglycemia-induced EndMT via reduced expression of ROS and inhibition of ROS-activated poly(ADP-ribose) polymerase 1 (PARP-1) [77]; (iii) high-density lipoprotein (HDL) inhibition of TGF-β1-induced EndMT [78]; (iv) endothelial heat shock protein beta-1 (HSPB-1)-mediated EndMT inhibition after stimulation with fibrotic cytokines [79]; (v) netrin-1-mediated attenuation of EndMT during renal dysfunction, as demonstrated in a nephrectomy rat model [80]; (vi) expression of ECM protein fibulin-1 via reduced expression of TGF-β2 [81]; (vii) secretion of cytokines and angiogenic factors by macrophages sustains endothelial differentiation of EPCs and consequently restricts EndMT during muscle regeneration [82].…”

Section: Introductionmentioning

confidence: 99%

The therapeutic potential of targeting the endothelial-to-mesenchymal transition

et al. 2018

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Endothelial cells (ECs) have been found to be capable of acquiring a mesenchymal phenotype through a process known as endothelial-to-mesenchymal transition (EndMT). First seen in the developing embryo, EndMT can be triggered postnatally under certain pathological conditions. During this process, ECs dedifferentiate into mesenchymal stem-like cells (MSCs) and subsequently give rise to cell types belonging to the mesoderm lineage. As EndMT contributes to a multitude of diseases, pharmacological modulation of the signaling pathways underlying EndMT may prove to be effective as a therapeutic treatment. Additionally, EndMT in ECs could also be exploited to acquire multipotent MSCs, which can be readily re-differentiated into various distinct cell types. In this review, we will consider current models of EndMT, how manipulation of this process might improve treatment of clinically important pathologies and how it could be harnessed to advance regenerative medicine and tissue engineering.

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Netrin-1 attenuates the progression of renal dysfunction by blocking endothelial-to-mesenchymal transition in the 5/6 nephrectomy rat model

Cited by 19 publications

References 30 publications

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin

Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

The therapeutic potential of targeting the endothelial-to-mesenchymal transition

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