scholarly journals Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells

2019 ◽  
Vol 316 (6) ◽  
pp. F1162-F1172 ◽  
Author(s):  
Qingqing Wei ◽  
Jennifer Su ◽  
Guie Dong ◽  
Ming Zhang ◽  
Yuqing Huo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Pathological Feature ◽  
Renal Interstitial Fibrosis ◽  
Tubular Cells ◽  
Glycolysis Inhibitors

Renal interstitial fibrosis is a common pathological feature of chronic kidney disease that may involve changes of metabolism in kidney cells. In the present study, we first showed that blockade of glycolysis with either dichloroacetate (DCA) or shikonin to target different glycolytic enzymes reduced renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). Both inhibitors evidently suppressed the induction of fibronectin and collagen type I in obstructed kidneys, with DCA also showing inhibitory effects on collagen type IV and α-smooth muscle actin (α-SMA). Histological examination also confirmed less collagen deposition in DCA-treated kidneys. Both DCA and shikonin significantly inhibited renal tubular apoptosis but not interstitial apoptosis in UUO. Macrophage infiltration after UUO injury was also suppressed. Shikonin, but not DCA, caused obvious animal weight loss during UUO. To determine whether shikonin and DCA worked on tubular cells and/or fibroblasts, we tested their effects on cultured renal proximal tubular BUMPT cells and renal NRK-49F fibroblasts during hypoxia or transforming growth factor-β1 treatment. Although both inhibitors reduced fibronectin and α-SMA production in NRK-49F cells during hypoxia or transforming growth factor-β1 treatment, they did not suppress fibronectin and α-SMA expression in BUMPT cells. Altogether, these results demonstrate the inhibitory effect of glycolysis inhibitors on renal interstitial fibrosis. In this regard, DCA is more potent for fibrosis inhibition and less toxic to animals than shikonin.

scholarly journals The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

2006 ◽  
Vol 26 (12) ◽  
pp. 4577-4585 ◽  
Author(s):  
Jingmei Lin ◽  
Sanjeevkumar R. Patel ◽  
Min Wang ◽  
Gregory R. Dressler
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Bmp Signaling ◽  
Cell Junctions ◽  
Type I ◽  
Renal Interstitial Fibrosis ◽  
Tgf Β1

ABSTRACT The transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) and TGF-β/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-β but inhibited by BMP7. In this report, the effects of KCP on TGF-β/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-β1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-β1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-β and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-β activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats

2014 ◽  
Vol 306 (12) ◽  
pp. F1477-F1488 ◽  
Author(s):  
Tian-Biao Zhou ◽  
Chao Ou ◽  
Yuan-Han Qin ◽  
Feng-Ying Lei ◽  
Wei-Fang Huang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Caspase 3 ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Collagen Type Iii ◽  
Renal Interstitial Fibrosis ◽  
Homeobox Transcription Factor

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM homeodomain type and has been implicated in the development of diverse structures such as limbs, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30% of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and renal interstitial fibrosis, we explored if LMX1B affects typical markers of fibrosis, e.g., extracellular matrix components, profibrotic factors, and apoptosis as the final detrimental consequence. We recently showed that LMX1B acts as a negative regulator of transforming growth factor-βl, collagen type III, fibronectin, cleaved caspase-3, and the cell apoptosis rate in a renal tubular epithelial cell system under hypoxic conditions. Here, we confirmed these results in unilateral ureteral obstructed rats. Furthermore, LMX1B was distinctly expressed throughout the glomerulus and tubule lining, including epithelial cells. Knockdown of LMX1B aggravated the expression of fibrosis markers, oxidative stress, and apoptosis compared with the already increased levels due to unilateral ureteral obstruction, whereas overexpression attenuated these effects. In conclusion, reduced LMX1B levels clearly represent a risk factor for renal fibrosis, whereas overexpression affords some level of protection. In general, LMX1B may be considered to be a negative regulator of the fibrosis index, transforming growth factor-βl, collagen type III, fibronectin, cleaved caspase-3, cell apoptosis, ROS, and malondialdehyde ( r = −0.756, −0.698, −0.921, −0.923, −0.843, −0.794, −0.883, and −0.825, all P < 0.01).

scholarly journals Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling

2013 ◽  
Vol 126 (4) ◽  
pp. 275-288 ◽  
Author(s):  
Hangxiang Zhang ◽  
Jing Wu ◽  
Hailong Dong ◽  
Shaukat A. Khan ◽  
Mon-Li Chu ◽  
...  
Keyword(s):  
Body Weight ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Cardiac Hypertrophy ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Matrix Metalloproteinase 2 ◽  
Type I

AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2−/−), heterozygous (Fbln2+/−) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2−/− showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2−/− mice. The Fbln2+/− mice consistently displayed AngII-induced effects intermediate between WT and Fbln2−/−. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2−/− mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2−/− cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac hypertrophy via enhanced TGF-β activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.

Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis

2000 ◽  
Vol 278 (4) ◽  
pp. F554-F560 ◽  
Author(s):  
Shi-Nong Wang ◽  
Raimund Hirschberg
Keyword(s):  
Renal Failure ◽  
Diabetic Nephropathy ◽  
Chronic Renal Failure ◽  
Growth Factor ◽  
Collagen Type ◽  
Interstitial Fibrosis ◽  
Collagen Type Iii ◽  
Renal Interstitial Fibrosis ◽  
Tubular Cells ◽  
Ecm Proteins

Glomerular proteinuria is a risk factor for progression of chronic renal failure and contributes to renal interstitial fibrosis. In experimental diabetic glomerular sclerosis, there is translocation of high-molecular-weight growth factors, namely, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-β, from plasma into tubular fluid, both of which act on tubular cells through apical membrane receptors. In the present studies, the hypothesis is examined that ultrafiltered HGF and TGF-β induce increased expression of extracellular matrix (ECM) proteins directly in tubular cells, or induce increased expression of cytokines that may act on interstitial myofibroblasts. Incubation of cultured tubular cells with recombinant human (rh) TGF-β modestly raises expression of collagen type III, but rhHGF dose dependently blocks expression of this ECM protein. Both growth factors raise fibronectin expression up to fourfold and increase expression of platelet-derived growth factor (PDGF)-BB up to sixfold, but not of fibroblast growth factor-2. Pooled, diluted glomerular ultrafiltrate that had been collected by nephron micropuncture from rats with diabetic nephropathy (24–30 wk) also raises expression of fibronectin as well as PDGF-BB in proximal tubular cells. In the presence of neutralizing antibodies that block actions of HGF and TGF-β, diabetic rat glomerular ultrafiltrate fails to increase tubular cell PDGF-BB expression. In NRK-49F renal interstitial myofibroblasts, rhPDGF-BB, in turn, raises the expression of collagen type III but not type I or fibronectin. The findings provide evidence for ultrafiltered HGF and TGF-β to contribute to interstitial accumulation of ECM proteins by direct effects on tubular cells as well as indirect mechanisms, via PDGF-BB and its action on myofibroblasts. These events may be important mechanisms of proteinuria-induced renal interstitial fibrosis and accelerated progression of chronic renal failure in diabetic nephropathy and perhaps other proteinuric glomerular diseases.

scholarly journals BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD

2019 ◽  
Vol 317 (6) ◽  
pp. F1430-F1438 ◽  
Author(s):  
Mi Bai ◽  
Juan Lei ◽  
Shuqin Wang ◽  
Dan Ding ◽  
Xiaowen Yu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Collagen Type I ◽  
Type I ◽  
Tubular Cells ◽  
Morphogenetic Protein ◽  
Proximal Tubular

Renal fibrosis is a key pathological phenomenon of chronic kidney disease (CKD) contributing to the progressive loss of renal function. UK383,367 is a procollagen C proteinase inhibitor that has been selected as a candidate for dermal antiscarring agents, whereas its role in renal fibrosis is unclear. In the present study, UK383,367 was applied to a CKD mouse model of unilateral ureteral obstruction (UUO) and cell lines of renal tubular epithelial cells (mouse proximal tubular cells) and renal fibroblast cells (NRK-49F cells) challenged by transforming growth factor-β1. In vivo, bone morphogenetic protein 1, the target of UK383,367, was significantly enhanced in UUO mouse kidneys and renal biopsies from patients with CKD. Strikingly, UK383,367 administration ameliorated tubulointerstitial fibrosis as shown by Masson’s trichrome staining in line with the blocked expression of collagen type I/III, fibronectin, and α-smooth muscle actin in the kidneys from UUO mice. Similarly, the enhanced inflammatory factors in obstructed kidneys were also blunted. In vitro, UK383,367 pretreatment inhibited the induction of collagen type I/III, fibronectin, and α-smooth muscle actin in both mouse proximal tubular cells and NRK-49F cells treated with transforming growth factor-β1. Taken together, these findings indicate that the bone morphogenetic protein 1 inhibitor UK383,367 could serve as a potential drug in antagonizing CKD renal fibrosis by acting on the maturation and deposition of collagen and the subsequent profibrotic response and inflammation.

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