Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial–Mesenchymal Transition

Zhang, Yanhong; Yin, Ning; Sun, Anbang; Wu, Qiming; Hu, Wenzhu; Hou, Xin; Zeng, Xixi; Zhu, Min; Liao, Yanhong

doi:10.3389/fcell.2020.602703

Cited by 11 publications

(14 citation statements)

References 102 publications

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“…Daria et al reported that TRPC6 participates in the regulation of podocyte Ca 2+ and renal damage in diabetic kidney disease ( Ilatovskaya et al, 2018 ). Besides, our recent study showed that TRPC6 regulates the epithelial–mesenchymal transition of TECs and relates to kidney fibrosis ( Zhang et al, 2020 ). Taken together, these studies showed the same results that TRPC6 blockage plays a beneficial role under pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

Hou

Huang

Zeng

et al. 2021

Front. Mol. Biosci.

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Renal ischemia/reperfusion (I/R), a major cause of acute kidney injury (AKI), is a serious clinical event in patients during post-renal transplantation. I/R is associated with renal dysfunction and tubular apoptosis, and calcium (Ca2+) overload has been reported to be a crucial factor on tubular apoptosis in I/R injury (IRI). The canonical transient receptor potential channel 6 (TRPC6), a type of non-selective Ca2+ channel, is involved in many renal diseases. Our earlier study identified that TRPC6-mediated Ca2+ influx plays a novel role in suppressing cytoprotective autophagy triggered by oxidative stress in primary tubular epithelial cells (TECs). This study explored the potential beneficial impact of TRPC6 knockout (TRPC6−/−) and the relevant cellular mechanisms against I/R-induced AKI in mice. Measuring changes of renal function, apoptotic index, and autophagy in mouse kidneys that suffered 24 h reperfusion after 40 min ischemia and working in vitro with TECs that suffered 24 h reoxygenation after 24 h hypoxia, we found that 1) IRI tissues had increased TRPC6 expression and TRPC6 knockout significantly ameliorated renal damage induced by IRI; 2) TRPC6 knockout enhanced the level of autophagy and alleviated the depolarization of mitochondrial membrane potential (ψm, MMP) and apoptotic changes upon IRI; and 3) IRI tissues had increased p-AKT and p-ERK1/2 expressions, while TRPC6 knockout could markedly reduce the phosphorylation of AKT and ERK1/2. These discoveries suggest that, by reducing Ca2+ overload, the underlying protective mechanism of TRPC6−/− may be involved in down-regulation of PI3K/AKT and ERK signaling, which is likely to provide a new avenue for future AKI therapies.

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Section: Discussionmentioning

confidence: 99%

The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

Hou

Huang

Zeng

et al. 2021

Front. Mol. Biosci.

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“…Previous studies have illustrated that the abnormal activation of AKT/mTOR pathway was implicated with oxidative stress and EMT [ 29 , 30 ]. Here, our data disclosed that PM2.5 stimulation significantly promoted the phosphorylation of AKT and mTOR in lung tissues (Figures 4(a) – 4(c) ).…”

Section: Resultsmentioning

confidence: 99%

Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

Zhongyin

Wang

Juan

et al. 2022

Oxidative Medicine and Cellular Longevity

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Oxidative damage and epithelial-mesenchymal transition (EMT) are main pathological processes leading to the development of PM2.5-induced lung fibrosis. Epigallocatechin gallate (EG), a natural polyphenol extracted from green tea, possesses the ability to combat oxidative stress and inflammation. However, the potential roles of EG in PM2.5-induced lung fibrosis have not been reported yet. In the present study, we investigated whether EG could relieve PM2.5-induced lung injury and fibrosis in vivo and in vitro. To mimic PM2.5-induced lung fibrosis, C57/BL6 mice were intranasally instilled with PM2.5 suspension, and MLE-12 lung epithelial cells were stimulated with PM2.5 (100 μg/mL) in vitro. The results showed that intragastric administration of EG (20 mg/kg/d or 80 mg/kg/d for 8 weeks) significantly prevented lung injury, inflammation, and oxidative stress in PM2.5-induced mice, apart from inhibiting collagen deposition. Additionally, EG treatment also suppressed the activation of AKT/mTOR signaling pathway in lung tissues challenged with PM2.5. In vitro experiments further demonstrated that EG treatment could enhance cell viability in a concentration-dependent manner in PM2.5-treated MLE-12 lung epithelial cells. Also, the overexpression of constitutively active AKT could offset the inhibitory effects of EG on EMT and oxidative stress in PM2.5-treated MLE-12 lung epithelial cells. Finally, AKT overexpression also blocked the inhibitory effect of EG on the phosphorylation of mTOR in PM2.5-treated MLE-12 lung epithelial cells. In conclusion, EG could improve PM2.5-induced lung fibrosis by decreasing oxidative damage and EMT through AKT/mTOR pathway, which might be a potential candidate for the treatment of PM2.5-induced lung fibrosis.

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“…TRPC6 has been implicated in the development of fibrosis in several organs. [35, 65-69, 79] In the kidney, both genetic,[35, 67] and pharmacologic,[66] inhibition of TRPC6 is reported to dampen the fibrotic response in the unilateral ureteral obstruction model. We were therefore somewhat surprised that the Trpc6 E896K/E896K mice do not show an increased fibrotic reaction after folate-induced AKI.…”

Section: Discussionmentioning

confidence: 99%

“…TRPC6 has been implicated in the development of fibrosis in several organs. [35,[63][64][65][66][67]77] In the kidney, both genetic, [35,65] and pharmacologic, [64] inhibition of TRPC6 is reported to dampen the fibrotic response in the unilateral ureteral obstruction model.…”

Section: Discussionmentioning

confidence: 99%

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Gain-of-function, focal segmental glomerulosclerosis Trpc6 mutation minimally affects susceptibility to renal injury in several mouse models

Brown

Boekell

Stotter

et al. 2022

Preprint

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Mutations in TRPC6 are a cause of autosomal dominant focal segmental glomerulosclerosis in humans. Many of these mutations are known to have a gain-of-function effect on the non-specific cation channel function of TRPC6. In vitro studies have suggested these mutations affect several signaling pathways, but in vivo studies have largely compared wild-type and Trpc6-deficient rodents. We developed mice carrying a gain-of-function Trpc6 mutation encoding an E896K amino acid change, corresponding to a known FSGS mutation in TRPC6. Homozygous mutant Trpc6 animals have no appreciable renal pathology, and do not develop albuminuria until very advanced age. The animals show a slight delay in recovery from the albumin overload model. In response to chronic angiotensin II infusion, the mice have slightly greater albuminuria initially compared to wild-type animals, an effect that is lost at later time points, and a statistically non-significant trend toward more glomerular injury. This phenotype is nearly opposite to that of Trpc6-deficient animals previously described. The Trpc6 mutation does not appreciably impact renal interstitial fibrosis in response to either angiotensin II infusion, or folate-induced kidney injury. TRPC6 protein and TRPC6-agonist induced calcium influx could not be detected in glomeruli. In sum, these findings suggest that gain-of-function Trpc6 mutations confer only a mild susceptibility to glomerular injury in the mouse.

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Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial–Mesenchymal Transition

Cited by 11 publications

References 102 publications

The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

Gain-of-function, focal segmental glomerulosclerosis Trpc6 mutation minimally affects susceptibility to renal injury in several mouse models

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