Activation of the cytosolic calcium-independent phospholipase A2 β isoform contributes to TRPC6 externalization via release of arachidonic acid

Putta, Priya; Smith, Andrew H.; Chaudhuri, Pinaki; Guardia-Wolff, Rocio; Rosenbaum, Michael; Graham, Linda M.

doi:10.1016/j.jbc.2021.101180

Cited by 9 publications

(5 citation statements)

References 41 publications

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“…Enhanced expression of TRPC6 was found in human urinary protein nephropathy such as IMN (19), while sublytic C5b-9 mediated elevated expression of TRPC6 in cultured podocytes in vitro (20). The combination of PLA2R on podocytes and anti-PLA2R antibodies activated the TRPC6 channel and increased the expression of TRPC6, resulting in the structural and functional impairment of podocytes (33). In the present study, increased expression of TRPC6 was detected in sublytic C5b-9-induced podocytes.…”

Section: Discussionsupporting

confidence: 57%

Downregulation of TRPC6 regulates ERK1/2 to prevent sublytic C5b‑9 complement complex‑induced podocyte injury through activating autophagy

Li,

Fang,

Liu

2023

Exp Ther Med

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Idiopathic membranous nephropathy (IMN) is a common glomerular disease, in which 50-60% of patients can progress to end-stage renal disease within 10-20 years, seriously endangering human health. Podocyte injury is the direct cause of IMN. Sublytic C5b-9 complement complex induces damage in podocytes' structure and function. In sublytic C5b-9 treated podocytes, the expression of canonical transient receptor potential 6 (TRPC6) is increased. However, the specific mechanism of TRPC6 in sublytic C5b-9 treated podocytes is unclear. The present study aimed to reveal the effect and mechanism of TRPC6 on sublytic C5b-9-induced podocytes. Normal human serum was stimulated using zymosan to form C5b-9. A lactate dehydrogenase release assay was used to examine C5b-9 cytotoxicity in podocytes. The RNA and protein expression levels were analyzed using reverse transcription-quantitative PCR, western blotting and immunofluorescent assay, respectively. Cell Counting Kit-8 assay and flow cytometry were carried out to test the viability and apoptosis of podocytes, respectively. Transmission electron microscopy was used to observe autophagic vacuole. F-actin was tested through phalloidin staining. Sublytic C5b-9 was deposited and TRPC6 expression was boosted in podocytes stimulated through zymosan activation serum. Knockdown of TRPC6 raised the viability and reduced the apoptosis rate of sublytic C5b-9-induced podocytes. Meanwhile, transfection of small-interfering (si)TRPC6 facilitated autophagy progression and enhanced the activation of cathepsin B/L in sublytic C5b-9-induced podocytes. The phosphorylation level of ERK1/2 was receded in siTRPC6 and sublytic C5b-9 co-treated podocytes. Moreover, the addition of the ERK1/2 activator partially reversed the effect of TRPC6 inhibition on sublytic C5b-9-induced podocytes. TRPC6 knockdown reduced the damage of sublytic C5b-9 to podocytes by weakening the ERK1/2 phosphorylation level to activate autophagy. These results indicated that targeting TRPC6 reduced the injury of sublytic C5b-9 on podocytes.

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Section: Discussionsupporting

confidence: 57%

Downregulation of TRPC6 regulates ERK1/2 to prevent sublytic C5b‑9 complement complex‑induced podocyte injury through activating autophagy

Li,

Fang,

Liu

2023

Exp Ther Med

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“…LysoPC is a significant pharmacodynamic marker associated with RAS efficacy in BD rats. It activates transient receptor potential 6 (TRPC6) channels, which in turn trigger the lipid-cleaving enzyme phospholipase A2 (PLA2) to release AA from cellular membranes, allowing calcium influx ( Putta et al, 2021 ). The activation of the arachidonate lipoxygenase-15/12-hydroxyeicosatetraenoic acid (Alox15/12-HETE) signaling pathway during AA lipoxygenase metabolism serves to protect calcified blood vessels ( Han et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Anti-platelet aggregation activities of different grades of Angelica sinensis and their therapeutic mechanisms in rats with blood deficiency: insights from metabolomics and lipidomics analyses

Shen,

Wu,

Chen

et al. 2024

Front. Pharmacol.

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In traditional Chinese medicine, the radix of Angelica sinensis (Oliv.) Diels (RAS) is mainly used to replenish and invigorate the blood circulation. This study investigated anti-platelet aggregation activities were used by New Zealand rabbits, and high-performance liquid chromatography data were obtained to determine the spectrum–effect relationship for different commercial grades of RAS. Plasma and urine metabolites were examined using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry-based metabolomics to elucidate the mechanisms underlying the role of these metabolites in a rat model of blood deficiency (BD). Plasma and spleen metabolites were additionally examined using ultra-performance liquid chromatography plus Q-Exactive tandem mass spectrometry-based lipidomics to clarify the mechanisms of RAS in treating BD. The third grade of RAS exhibited the best activity in replenishing and invigorating blood in vitro and in vivo. Ferulic acid, ligustilide, senkyunolide I, uridine, and guanine are quality markers of anti-platelet aggregation activity. Based on the metabolomics results, 19 potential biomarkers were screened in plasma, and 12 potential metabolites were detected in urine. In lipidomics analyses, 73 potential biomarkers were screened in plasma, and 112 potential biomarkers were screened in the spleen. RAS may restore lipid metabolism by regulating disorders of glycerophospholipid and sphingolipid metabolism, the tricarboxylic acid cycle, amino acid metabolism (thereby improving energy metabolism), and arachidonic acid metabolism (thereby promoting blood circulation). These results provide a deeper understanding of the effects of different grades of RAS and a scientific reference for the establishment of grading standards and for the clinical use of RAS.

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“…Development of cell polarity directs exocytosis at specialized sites of membrane growth [83,84]. In this context, it is important to note that AA and DHA and their metabolites participate and regulate neurite growth and neurotransmitters exocytosis, insulin and renin secretion, immune surveillance, cell migration, wound healing and cell growth and multiplication [6][7][8][9][10][11][12][13][14]61,[71][72][73][74][75][76][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99]. These results coupled with the observation that alterations in the pressure or stretch leads to an alteration in the nuclear membrane tension that triggers calcium release, cPLA2 activation and release of AA [4,5] implies the role of AA to function as a mechanotransducer.…”

Section: Conclusion and Therapeutic Implicationsmentioning

confidence: 99%

Arachidonic Acid as Mechanotransducer of Renin Cell Baroreceptor

Das¹

2022

Nutrients

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For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as the situation demands by the juxtaglomerular cells (also called as granular cells) that are in the walls of the afferent arterioles. Juxtaglomerular cells can sense minute changes in the blood pressure and blood volume and accordingly synthesize, store, and secrete appropriate amounts of renin. Thus, when the blood pressure and blood volume are decreased JGA cells synthesize and secrete higher amounts of renin and when the blood pressure and blood volume is increased the synthesis and secretion of renin is decreased such that homeostasis is restored. To decipher this important function, JGA cells (renin cells) need to sense and transmit the extracellular physical forces to their chromatin to control renin gene expression for appropriate renin synthesis. The changes in perfusion pressure are sensed by Integrin β1 that is transmitted to the renin cell’s nucleus via lamin A/C that produces changes in the architecture of the chromatin. This results in an alteration (either increase or decrease) in renin gene expression. Cell membrane is situated in an unique location since all stimuli need to be transmitted to the cell nucleus and messages from the DNA to the cell external environment can be conveyed only through it. This implies that cell membrane structure and integrity is essential for all cellular functions. Cell membrane is composed to proteins and lipids. The lipid components of the cell membrane regulate its (cell membrane) fluidity and the way the messages are transmitted between the cell and its environment. Of all the lipids present in the membrane, arachidonic acid (AA) forms an important constituent. In response to pressure and other stimuli, cellular and nuclear shape changes occur that render nucleus to act as an elastic mechanotransducer that produces not only changes in cell shape but also in its dynamic behavior. Cell shape changes in response to external pressure(s) result(s) in the activation of cPLA2 (cytosolic phospholipase 2)-AA pathway that stretches to recruit myosin II which produces actin-myosin cytoskeleton contractility. Released AA can undergo peroxidation and peroxidized AA binds to DNA to regulate the expression of several genes. Alterations in the perfusion pressure in the afferent arterioles produces parallel changes in the renin cell membrane leading to changes in renin release. AA and its metabolic products regulate not only the release of renin but also changes in the vanilloid type 1 (TRPV1) expression in renal sensory nerves. Thus, AA and its metabolites function as intermediate/mediator molecules in transducing changes in perfusion and mechanical pressures that involves nuclear mechanotransduction mechanism. This mechanotransducer function of AA has relevance to the synthesis and release of insulin, neurotransmitters, and other soluble mediators release by specialized and non-specialized cells. Thus, AA plays a critical role in diseases such as diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, sepsis, lupus, rheumatoid arthritis, and cancer.

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Activation of the cytosolic calcium-independent phospholipase A2 β isoform contributes to TRPC6 externalization via release of arachidonic acid

Cited by 9 publications

References 41 publications

Downregulation of TRPC6 regulates ERK1/2 to prevent sublytic C5b‑9 complement complex‑induced podocyte injury through activating autophagy

Downregulation of TRPC6 regulates ERK1/2 to prevent sublytic C5b‑9 complement complex‑induced podocyte injury through activating autophagy

Anti-platelet aggregation activities of different grades of Angelica sinensis and their therapeutic mechanisms in rats with blood deficiency: insights from metabolomics and lipidomics analyses

Arachidonic Acid as Mechanotransducer of Renin Cell Baroreceptor

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