Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney

In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-β and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

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Targeting TGF-β Signaling in Kidney Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms19092532 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2532 ◽

Cited By ~ 38

Author(s):

Yoshitaka Isaka

Keyword(s):

Intracellular Signaling ◽

Renal Fibrosis ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Kidney Diseases ◽

Transforming Growth Factor Β ◽

Cell Interaction ◽

Common Pathway ◽

Kidney Fibrosis ◽

Fibrotic Diseases

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of production, activation, binding to the receptor, and intracellular signaling, have been developed. Some of them were examined in clinical studies against kidney fibrosis, and some are applied to other fibrotic diseases or cancer. Here, I review the approaches targeting TGF-β signaling in kidney fibrosis.

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TGF-β signaling in the kidney: profibrotic and protective effects

AJP Renal Physiology ◽

10.1152/ajprenal.00365.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. F596-F606 ◽

Cited By ~ 74

Author(s):

Angara Sureshbabu ◽

Saif A. Muhsin ◽

Mary E. Choi

Keyword(s):

Renal Fibrosis ◽

Transforming Growth Factor ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Therapeutic Strategies ◽

Protective Effects ◽

Successful Therapy ◽

Protective Response ◽

Pharmacological Blockade ◽

Fibrotic Diseases

Transforming growth factor-β (TGF-β) is generally considered as a central mediator of fibrotic diseases. Indeed, much focus has been placed on inhibiting TGF-β and its downstream targets as ideal therapeutic strategies. However, pharmacological blockade of TGF-β has not yet translated into successful therapy for humans, which may be due to pleiotropic effects of TGF-β signaling. Equally, TGF-β signaling as a protective response in kidney injury has been relatively underexplored. An emerging body of evidence from experimental kidney disease models indicates multifunctionality of TGF-β capable of inducing profibrotic and protective effects. This review discusses recent advances highlighting the diverse roles of TGF-β in promoting not only renal fibrosis but also protective responses of TGF-β signaling. We review, in particular, growing evidence that supports protective effects of TGF-β by mechanisms which include inhibiting inflammation and induction of autophagy. Additional detailed studies are required to fully understand the diverse mechanisms of TGF-β actions in renal fibrosis and inflammation that will likely direct toward effective antifibrotic therapies.

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The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis

Clinical Science ◽

10.1042/cs20200923 ◽

2020 ◽

Vol 134 (21) ◽

pp. 2873-2891

Author(s):

Sarah W.Y. Lok ◽

Wai Han Yiu ◽

Hongyu Li ◽

Rui Xue ◽

Yixin Zou ◽

...

Keyword(s):

Epithelial Cells ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Tubules ◽

Tubular Epithelial Cells ◽

Kidney Fibrosis ◽

Mesenchymal Transition

Abstract Protease-activated receptor (PAR)-1 has emerged as a key profibrotic player in various organs including kidney. PAR-1 activation leads to deposition of extracellular matrix (ECM) proteins in the tubulointerstitium and induction of epithelial–mesenchymal transition (EMT) during renal fibrosis. We tested the anti-fibrotic potential of vorapaxar, a clinically approved PAR-1 antagonist for cardiovascular protection, in an experimental kidney fibrosis model of unilateral ureteral obstruction (UUO) and an AKI-to-chronic kidney disease (CKD) transition model of unilateral ischemia–reperfusion injury (UIRI), and dissected the underlying renoprotective mechanisms using rat tubular epithelial cells. PAR-1 is activated mostly in the renal tubules in both the UUO and UIRI models of renal fibrosis. Vorapaxar significantly reduced kidney injury and ameliorated morphologic changes in both models. Amelioration of kidney fibrosis was evident from down-regulation of fibronectin (Fn), collagen and α-smooth muscle actin (αSMA) in the injured kidney. Mechanistically, inhibition of PAR-1 inhibited MAPK ERK1/2 and transforming growth factor-β (TGF-β)-mediated Smad signaling, and suppressed oxidative stress, overexpression of pro-inflammatory cytokines and macrophage infiltration into the kidney. These beneficial effects were recapitulated in cultured tubular epithelial cells in which vorapaxar ameliorated thrombin- and hypoxia-induced TGF-β expression and ECM accumulation. In addition, vorapaxar mitigated capillary loss and the expression of adhesion molecules on the vascular endothelium during AKI-to-CKD transition. The PAR-1 antagonist vorapaxar protects against kidney fibrosis during UUO and UIRI. Its efficacy in human CKD in addition to CV protection warrants further investigation.

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Temporal transcriptomic profiling reveals dynamic changes in gene expression of Xenopus animal cap upon activin treatment

Scientific Reports ◽

10.1038/s41598-021-93524-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yumeko Satou-Kobayashi ◽

Jun-Dal Kim ◽

Akiyoshi Fukamizu ◽

Makoto Asashima

Keyword(s):

Time Course ◽

Transforming Growth Factor ◽

Transcriptome Profiling ◽

Transforming Growth Factor Β ◽

Activin A ◽

Cytokine Signaling ◽

Molecular Characteristics ◽

Transcriptional Dynamics

AbstractActivin, a member of the transforming growth factor-β (TGF-β) superfamily of proteins, induces various tissues from the amphibian presumptive ectoderm, called animal cap explants (ACs) in vitro. However, it remains unclear how and to what extent the resulting cells recapitulate in vivo development. To comprehensively understand whether the molecular dynamics during activin-induced ACs differentiation reflect the normal development, we performed time-course transcriptome profiling of Xenopus ACs treated with 50 ng/mL of activin A, which predominantly induced dorsal mesoderm. The number of differentially expressed genes (DEGs) in response to activin A increased over time, and totally 9857 upregulated and 6663 downregulated DEGs were detected. 1861 common upregulated DEGs among all Post_activin samples included several Spemann’s organizer genes. In addition, the temporal transcriptomes were clearly classified into four distinct groups in correspondence with specific features, reflecting stepwise differentiation into mesoderm derivatives, and a decline in the regulation of nuclear envelop and golgi. From the set of early responsive genes, we also identified the suppressor of cytokine signaling 3 (socs3) as a novel activin A-inducible gene. Our transcriptome data provide a framework to elucidate the transcriptional dynamics of activin-driven AC differentiation, reflecting the molecular characteristics of early normal embryogenesis.

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Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Cells ◽

10.3390/cells10082070 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2070

Author(s):

Pasquale Esposito ◽

Daniela Verzola ◽

Daniela Picciotto ◽

Leda Cipriani ◽

Francesca Viazzi ◽

...

Keyword(s):

Vascular Calcification ◽

Intracellular Signaling ◽

Transforming Growth Factor ◽

Vascular Inflammation ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Activin A ◽

Premature Aging ◽

High Morbidity ◽

Type I

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

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Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis

Journal of Biological Chemistry ◽

10.1074/jbc.m113.492793 ◽

2013 ◽

Vol 288 (52) ◽

pp. 37319-37331 ◽

Cited By ~ 52

Author(s):

Hyunjae Chung ◽

Rithwik Ramachandran ◽

Morley D. Hollenberg ◽

Daniel A. Muruve

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Signaling Pathways ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Growth Factor Receptor ◽

Transforming Growth Factor Β ◽

Epidermal Growth ◽

Β Receptor

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Urine Biomarkers to Predict Response to Lupus Nephritis Therapy in Children and Young Adults

The Journal of Rheumatology ◽

10.3899/jrheum.161128 ◽

2017 ◽

Vol 44 (8) ◽

pp. 1239-1248 ◽

Cited By ~ 17

Author(s):

Hermine I. Brunner ◽

Michael R. Bennett ◽

Gaurav Gulati ◽

Khalid Abulaban ◽

Marisa S. Klein-Gitelman ◽

...

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Transforming Growth Factor ◽

Kidney Biopsy ◽

Characteristic Curve ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Response To Therapy ◽

Spot Urine ◽

Urine Biomarkers

Objective.To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN).Methods.Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-β (TGF-β), transferrin, and vitamin D binding protein (VDBP).Results.Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-β (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups.Conclusion.Low urine levels of TGF-β and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.

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TAK1 deficiency attenuates cisplatin-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00516.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. F209-F215 ◽

Cited By ~ 2

Author(s):

Jun Zhou ◽

Changlong An ◽

Xiaogao Jin ◽

Zhaoyong Hu ◽

Robert L. Safirstein ◽

...

Keyword(s):

Acute Kidney Injury ◽

Proximal Tubule ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Tubular Epithelial Cell ◽

Tubular Damage ◽

Wild Type ◽

Deficient Mice

Cisplatin can cause acute kidney injury (AKI), but the molecular mechanisms are not well understood. The objective of the present study was to examine the role of transforming growth factor-β-activated kinase-1 (TAK1) in the pathogenesis of cisplatin-induced AKI. Wild-type mice and proximal tubule TAK1-deficient mice were treated with vehicle or cisplatin. Compared with wild-type control mice, proximal tubule TAK1-deficient mice had less severe kidney dysfunction, tubular damage, and apoptosis after cisplatin–induced AKI. Furthermore, conditional disruption of TAK1 in proximal tubular epithelial cells reduced caspase-3 activation, proinflammatory molecule expression, and JNK phosphorylation in the kidney in cisplatin-induced AKI. Taken together, cisplatin activates TAK1-JNK signaling pathway to promote tubular epithelial cell apoptosis and inflammation in cisplatin-induced AKI. Targeting TAK1 could be a novel therapeutic strategy against cisplatin-induced AKI.

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Antifibrotic Potential of MiR-335-3p in Hereditary Gingival Fibromatosis

Journal of Dental Research ◽

10.1177/0022034519863300 ◽

2019 ◽

Vol 98 (10) ◽

pp. 1140-1149 ◽

Cited By ~ 1

Author(s):

Q. Gao ◽

K. Yang ◽

D. Chen ◽

Y. Song ◽

W. Qiao ◽

...

Keyword(s):

Large Scale ◽

Target Genes ◽

Transforming Growth Factor ◽

Target Prediction ◽

Transforming Growth Factor Β ◽

Human Gingival Fibroblasts ◽

High Recurrence Rate ◽

Gingival Fibroblasts ◽

New Paradigm ◽

Gingival Fibromatosis

Hereditary gingival fibromatosis (HGF) is a highly genetically heterogeneous disease, and current therapeutic method is limited to surgical resection with a high recurrence rate. MicroRNAs (miRNAs) are able to fine-tune large-scale target genes. Here we established a simple but effective computational strategy based on available miRNA target prediction algorithms to pinpoint the most potent miRNA that could negatively regulate a group of functional genes. Based on this rationale, miR-335-3p was top ranked by putatively targeting 85 verified profibrotic genes and 79 upregulated genes in HGF patients. Experimentally, downregulation of miR-355-3p was demonstrated in HGF-derived gingival fibroblasts as well as in transforming growth factor β–stimulated normal human gingival fibroblasts (NHGFs) compared to normal control. Ectopic miR-335-3p attenuated, whereas knockdown of miR-335-3p promoted, the fibrogenic activity of human gingival fibroblasts. Mechanically, miR-335-3p directly targeted SOS1, SMAD2/3, and CTNNB1 by canonical and noncanonical base paring. In particular, different portfolios of fibrotic markers were suppressed by silencing SOS1, SMAD2/3, or CTNNB1, respectively. Thus, our study first proposes a novel miRNA screening approach targeting a functionally related gene set and identifies miR-335-3p as a novel target for HGF treatment. Mechanically, miR-335-3p suppresses the fibrogenic activity of human gingival fibroblasts by repressing multiple core molecules in profibrotic networks. Our strategy provides a new paradigm in the treatment for HGF as well as other diseases.

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