Mitochondrial TRPC3 promotes cell proliferation by regulating the mitochondrial calcium and metabolism in renal polycystin-2 knockdown cells

Li, Zhongxin; Zhou, Jingjing; Li, Yan; Yang, Fan; Lian, Xiaoying; Liu, Wenhu

doi:10.1007/s11255-019-02149-7

Cited by 10 publications

(10 citation statements)

References 49 publications

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“…Mitochondrial dysfunction exists from an early phase of ADPKD, suggesting a relationship between mitochondria function and ADPKD (6,7). More recently, as the study reported by Ishimoto et al, mitochondrial dysfunction facilitates the cyst formation in ADPKD (8,9), further indicating the vital function of mitochondria in cyst formation. It is widerecognized that there exists a structural and functional link between the mitochondrial network and the endoplasmic reticulum (ER) (10,11).…”

Section: Original Articlementioning

confidence: 79%

“…Respiration in IMCD3 cells and mitochondria was checked with high-resolution respirometry (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria) equipped with two chambers using a chamber volume set to 2 mL. The protocol was broadly following the previously published study (8). Briefly, IMCD3 cells were re-suspended in the MiR05 solution and transferred separately to oxygraph chambers at a density of 1×10 6 cells/mL.…”

Section: High-resolution Respirometrymentioning

confidence: 99%

“…Mitochondrial Ca 2+ uptake capacity was measured by using the protocol of mitochondrial Ca 2+ uptake assay, following the previously published study (8). Briefly, cells were digested and re-suspended using the extracellular solution.…”

Section: Mitochondrial Ca 2+ Uptake Assaymentioning

confidence: 99%

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Overexpression of DJ-1 alleviates autosomal dominant polycystic kidney disease by regulating cell proliferation, apoptosis, and mitochondrial metabolism in vitro and in vivo

Zhou

et al. 2020

Ann Transl Med

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Background: DJ-1 is critical for the mitochondrial function associated with autosomal dominant polycystic kidney disease (ADPKD). We aimed to investigate DJ-1's function in the pathogenesis of ADPKD.Methods: DJ-1 was knocked-down in IMCD3 cells to evaluate the effects of DJ-1 on cell phenotype and mitochondrial function in vitro. Furthermore, we generated three groups of mice with different expression levels of DJ-1 within an established ADPKD model: ADPKD, ADPKD pcDNA , and ADPKD pcDNA-DJ-1 .Results: DJ-1 knock-down significantly increased oxidative stress as well as the proliferation and apoptosis rate of IMCD3 cells, along with Bcl-2 down-regulation and the up-regulation of Ki67, PCNA, Bax, cleaved caspase-3, and cleaved caspase-9. DJ-1 knock-down suppressed the cellular respiration, Ca 2+ absorption, and mitochondrial complex I activity in mitochondria. In vivo, we verified that DJ-1 was down-regulated in ADPKD models, and its overexpression attenuated the renal dysfunction in ADPKD models. The transgenic mice had a significantly smaller renal cyst and less interstitial fibrosis than control, accompanied byα-SMA, fibronectin, and TGF-β1 up-regulation. Moreover, in vivo results confirmed DJ-1 overexpression inhibited the proliferation and apoptosis of tubular epithelial cells along with down-regulation of Ki67, PCNA, p53, intracellular Cyt c, cleaved caspase-3, and cleaved caspase-9 and the up-regulation of Bcl-2.Conclusions: DJ-1 was down-regulated in ADPKD models, and its overexpression may attenuate the renal dysfunction and pathological damage by regulating the proliferation, apoptosis, oxidative stress and mitochondrial metabolism, which may be mediated by the p53 signaling pathway.

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Section: Original Articlementioning

confidence: 79%

Section: High-resolution Respirometrymentioning

confidence: 99%

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Overexpression of DJ-1 alleviates autosomal dominant polycystic kidney disease by regulating cell proliferation, apoptosis, and mitochondrial metabolism in vitro and in vivo

Zhou

et al. 2020

Ann Transl Med

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“…Cellular Ca 2+ is altered by a decreased channel function resulting in the activation of the adenylate cyclase with generation of cAMP. The latter stimulates the protein kinase A and Ras/Raf/extracellular-regulated signaling kinase (ERK) pathway that promotes cellular proliferation and cystogenesis [157][158][159]. Current understanding of ADPKD pathogenesis is summarized in [155].…”

Section: Mitochondrial Trpc3 Drives Detrimental Calcium Uptake and Me...mentioning

confidence: 99%

TRPC Channels in the Physiology and Pathophysiology of the Renal Tubular System: What Do We Know?

Englisch

Paulsen

Tschernig

2022

IJMS

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The study of transient receptor potential (TRP) channels has dramatically increased during the past few years. TRP channels function as sensors and effectors in the cellular adaptation to environmental changes. Here, we review literature investigating the physiological and pathophysiological roles of TRPC channels in the renal tubular system with a focus on TRPC3 and TRPC6. TRPC3 plays a key role in Ca2+ homeostasis and is involved in transcellular Ca2+ reabsorption in the proximal tubule and the collecting duct. TRPC3 also conveys the osmosensitivity of principal cells of the collecting duct and is implicated in vasopressin-induced membrane translocation of AQP-2. Autosomal dominant polycystic kidney disease (ADPKD) can often be attributed to mutations of the PKD2 gene. TRPC3 is supposed to have a detrimental role in ADPKD-like conditions. The tubule-specific physiological functions of TRPC6 have not yet been entirely elucidated. Its pathophysiological role in ischemia-reperfusion injuries is a subject of debate. However, TRPC6 seems to be involved in tumorigenesis of renal cell carcinoma. In summary, TRPC channels are relevant in multiples conditions of the renal tubular system. There is a need to further elucidate their pathophysiology to better understand certain renal disorders and ultimately create new therapeutic targets to improve patient care.

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“…In the proximal tubule TRPC3 is believed to have a nephroprotective function with respect to the sequence of hypercalciuria, nephrocalcinosis, and potentially chronic kidney disease [34][35][36] . A pathogenic role in autosomal dominant proteinuric kidney disease (ADPKD) upon TRPP1/2 loss-of-function mutation has also been suggested 11,37 . In contrast to TRPC3 and TRPC6, reports on TRPC5 in the renal tubular system are either very rare or not existent.…”

Section: Introductionmentioning

confidence: 99%

New Insights in the Distribution Profile of TRPC3 and TRPC5 in the Mouse and Human Kidney

Diebolt,

Schaudien,

Junker

et al. 2023

Preprint

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Several reports previously investigated Transient Receptor Potential Canonical subfamily channels 3 and 5 (TRPC3/TRPC5) in the kidney. However, most of the conclusions are based on animal samples or cell cultures leaving the door open for human tissue investigations. Moreover, results often disagreed among investigators. Histological description is lacking since most of these studies focused on functional aspects. Nevertheless, the same reports highlighted the potential differing key-roles of TRPC3 or TRPC5 in various renal disorders. Hence, our interest to investigate the localization of TRPC3 and TRPC5 in human kidneys. For this purpose, both healthy mouse and human kidney samples that were originated from tumor nephrectomies have been prepared for immunohistochemical staining using knockout-tested antibodies. Blocking peptides confirmed antibody specificity. A normalized weighted diaminobenzidine (DAB) area score between 0–3 comparable to a pixelwise H-score was established and employed for semiquantitative analysis. Altogether, our results suggest that glomeruli only express little TRPC3 and TRPC5 compared to several segments of the tubular system. Cortical and medullary proximal tubules are strongly stained. Intermediate tubules, however, are only weakly stained. The distal tubule was studied in three different localizations and depending on species and primary antibody, the staining was marked although slightly varying throughout the different localizations. Finally, the collecting duct was independently of primary antibody more stained in human compared to mouse tissue. We provide evidence that TRPC3 and TRPC5 are differently expressed in various localizations in both mouse and human samples. Especially, the TRPC5 distribution profile, we present here is completely new to our knowledge and raises questions, for instance its physiological relevance in the tubular system. We less verify results of previous studies than propose until now undescribed localizations of TRPC3 and TRPC5 in the mouse but especially and of greater interest in the human kidney. We thereby not only support the translational concept of TRPC channels as key players in physiology and pathophysiology of the human kidney but also present new potential targets to functional analysis.

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Mitochondrial TRPC3 promotes cell proliferation by regulating the mitochondrial calcium and metabolism in renal polycystin-2 knockdown cells

Cited by 10 publications

References 49 publications

Overexpression of DJ-1 alleviates autosomal dominant polycystic kidney disease by regulating cell proliferation, apoptosis, and mitochondrial metabolism in vitro and in vivo

Overexpression of DJ-1 alleviates autosomal dominant polycystic kidney disease by regulating cell proliferation, apoptosis, and mitochondrial metabolism in vitro and in vivo

TRPC Channels in the Physiology and Pathophysiology of the Renal Tubular System: What Do We Know?

New Insights in the Distribution Profile of TRPC3 and TRPC5 in the Mouse and Human Kidney

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