Protective Effect of TRPV1 against Renal Fibrosis via Inhibition of TGF-β/Smad Signaling in DOCA-Salt Hypertension

Wang, Youping; Wang, Donna H.

doi:10.2119/molmed.2011.00063

Cited by 38 publications

(33 citation statements)

References 84 publications

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“…Supporting our findings, earlier studies on TRPV1 in odontoblasts and in sensory neurons showed that the TRPV1 signaling response is elicited through sequential activation of ERK1/2 MAPK and increases in expression of the transcription factor, Egr-1, leading to cyclin dependent kinase 5 (CDK5)-mediated TRPV1 phosphorylation, increases in Ca2+ influx and intracellular acidification leading to dental nociception [38,39]. On the other hand, TRPV1 activation by TGFβR suppresses progression of renal fibrosis caused by DOCA-induced salt dependent hypertension since in TRPV1 knockout mice fibrosis is reduced [40]. Similarly, in another study characterizing TRPV1 involvement in modulating the effect of TGFβR activation by myocardial infarction (MI) on survival, it was shown that TRPV1 has instead a protective role in the healing process by reducing fibrosis and improving contractile performance [41].…”

Section: Discussionmentioning

confidence: 99%

TRPV1 Potentiates TGFβ-Induction of Corneal Myofibroblast Development through an Oxidative Stress-Mediated p38-SMAD2 Signaling Loop

et al. 2013

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Injuring mouse corneas with alkali causes myofibroblast expression leading to tissue opacification. However, in transient receptor potential vanilloid 1 channel (TRPV1-/-) knockout mice healing results in transparency restoration. Since TGFβ is the primary inducer of the myofibroblast phenotype, we examined the mechanism by which TRPV1 affects TGFβ-induced myofibroblast development. Experiments were performed in pig corneas and human corneal fibroblasts (HCFs). Immunohistochemical staining of α-smooth muscle actin (α-SMA) stress fibers was used to visualize myofibroblasts. Protein and phosphoprotein were determined by Western blotting. siRNA transfection silenced TRPV1 gene expression. Flow cytometry with a reactive oxygen species (ROS) reporting dye analyzed intracellular ROS. [Ca2+]I was measured by loading HCF with fura2. In organ cultured corneas, the TRPV1 antagonist capsazepine drastically reduced by 75% wound-induced myofibroblast development. In HCF cell culture, TGF-β1 elicited rapid increases in Ca2+ influx, phosphorylation of SMAD2 and MAPKs (ERK1/2, JNK1/2 and p38), ROS generation and, after 72 hrs myofibroblast development. SMAD2 and p38 activation continued for more than 16 h, whereas p-ERK1/2 and p-JNK1/2 waned within 90 min. The long-lived SMAD2 activation was dependent on activated p38 and vice versa, and it was essential to generate a > 13-fold increase in α-SMA protein and a fully developed myofibroblast phenotype. These later changes were markedly reduced by inhibition of TRPV1 or reduction of the ROS generation rate. Taken together our results indicate that in corneal derived fibroblasts, TGFβ- induced myofibroblast development is highly dependent on a positive feedback loop where p-SMAD2-induced ROS activates TRPV1, TRPV1 causes activation of p38, the latter in turn further enhances the activation of SMAD2 to establish a recurrent loop that greatly extends the residency of the activated state of SMAD2 that drives myofibroblast development.

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Section: Discussionmentioning

confidence: 99%

TRPV1 Potentiates TGFβ-Induction of Corneal Myofibroblast Development through an Oxidative Stress-Mediated p38-SMAD2 Signaling Loop

et al. 2013

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“…). Moreover, activation of TRPV1 can lead to reduced renal injury in deoxycorticosterone acetate (DOCA)–salt hypertension (Wang & Wang , ). However, downstream signal transduction pathways and mechanisms are not entirely clear and may involve vascular and neuronal mechanisms.…”

Section: Transient Receptor Potential Channelsmentioning

confidence: 99%

Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2

et al. 2016

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Members of the transient receptor potential (TRP) cation channel receptor family have unique sites of regulatory function in the kidney which enables them to promote regional vasodilatation and controlled Ca influx into podocytes and tubular cells. Activated TRP vanilloid 1 receptor channels (TRPV1) have been found to elicit renoprotection in rodent models of acute kidney injury following ischaemia/reperfusion. Transient receptor potential cation channel, subfamily C, member 6 (TRPC6) in podocytes is involved in chronic proteinuric kidney disease, particularly in focal segmental glomerulosclerosis (FSGS). TRP vanilloid 4 receptor channels (TRPV4) are highly expressed in the kidney, where they induce Ca influx into endothelial and tubular cells. TRP melastatin (TRPM2) non-selective cation channels are expressed in the cytoplasm and intracellular organelles, where their inhibition ameliorates ischaemic renal pathology. Although some of their basic properties have been recently identified, the renovascular role of TRPV1, TRPV4, TRPC6 and TRPM2 channels in disease states such as obesity, hypertension and diabetes is largely unknown. In this review, we discuss recent evidence for TRPV1, TRPV4, TRPC6 and TRPM2 serving as potential targets for acute and chronic renoprotection in chronic vascular and metabolic disease.

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“…O'Conor, Leddy, Benefield, Liedtke, and Guilak () found that activation of TRPV4 by GSK101 could significantly enhance the ability of chondrocytes to accumulate ECM components, including s‐GAG and COL‐2. Furthermore, TRPV1 has been shown to regulate the composition of ECM in renal fibrosis (Wang & Wang, ). However, it is unclear whether TRPV6 is also involved in chondrocyte‐secreted ECM.…”

Section: Discussionmentioning

confidence: 99%

Regulation of chondrocyte functions by transient receptor potential cation channel V6 in osteoarthritis

Song

Guo

et al. 2017

Journal Cellular Physiology

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Transient receptor potential vanilloid (TRPV) channels function to maintain the dynamic balance of calcium signaling and calcium metabolism in bones. The goal of this study was to determine the potential role of TRPV6 in regulation of chondrocytes. The level of TRPV6 expression was analyzed by western blot in articular cartilage derived from the knee joints of osteoarthritis (OA) rat models and OA patients. Bone structure and osteoarthritic changes in the knee joints of TRPV6 knockout mice were examined using micro-computed and histological analysis at the age of 6 and 12 months old. Furthermore, to investigate the effects of TRPV6 on chondrocyte extracellular matrix secretion, the release of matrix degrading enzymes, cell proliferation, and apoptosis, we decreased and increased TRPV6 expression in chondrocytes with lentiviral constructs encoding shRNA targeting TRPV6 and encoding TRPV6, respectively. The results showed that the level of TRPV6 expression in an OA rat model was markedly down-regulated. TRPV6 knockout mice showed severe osteoarthritis changes, including cartilage fibrillation, eburnation, and loss of proteoglycans. In addition, deficiency of TRPV6 clearly affected chondrocyte function, such as extracellular matrix secretion, the release of matrix degrading enzymes, cell proliferation, and apoptosis. Taken together, our results implicated that TRPV6 channel, as a chondro-protective factor, was involved in the pathogenesis of OA.

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Protective Effect of TRPV1 against Renal Fibrosis via Inhibition of TGF-β/Smad Signaling in DOCA-Salt Hypertension

Cited by 38 publications

References 84 publications

TRPV1 Potentiates TGFβ-Induction of Corneal Myofibroblast Development through an Oxidative Stress-Mediated p38-SMAD2 Signaling Loop

TRPV1 Potentiates TGFβ-Induction of Corneal Myofibroblast Development through an Oxidative Stress-Mediated p38-SMAD2 Signaling Loop

Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2

Regulation of chondrocyte functions by transient receptor potential cation channel V6 in osteoarthritis

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