Quinomycin A reduces cyst progression in polycystic kidney disease

Radadiya, Priyanka S.; Thornton, Mackenzie; Daniel, Emily; Idowu, Jessica Y.; Wang, Wei; Magenheimer, Brenda S.; Subramaniam, Dharmalingam; Tran, Pamela V.; Calvet, James P.; Wallace, Darren P.; Sharma, Madhulika

doi:10.1096/fj.202002490r

Cited by 5 publications

(3 citation statements)

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“…HEYL, HEY1, and HES1 are effectors of the Notch pathway in fibrosis promotion [ 17 , 18 ] and are up‐regulated upon Notch signaling ligands binding to NOTCH receptors. [ 19 , 20 ] Here, we studied the expression of these genes during meniscus development.…”

Section: Resultsmentioning

confidence: 99%

Silencing of NOTCH3 Signaling in Meniscus Smooth Muscle Cells Inhibits Fibrosis and Exacerbates Degeneration in a HEYL‐Dependent Manner

et al. 2023

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The mechanisms of meniscus fibrosis and novel ways to enhance fibrosis is unclear. This work reveals human meniscus fibrosis initiated at E24 weeks. Smooth muscle cell cluster is identified in embryonic meniscus, and the combined analysis with previous data suggests smooth muscle cell in embryonic meniscus as precursors of progenitor cells in the mature meniscus. NOTCH3 is constantly expressed in smooth muscle cells throughout embryogenesis to adulthood. Inhibition of NOTCH3 signaling in vivo inhibits meniscus fibrosis and exacerbates degeneration. Continuous histological sections show that HEYL, NOTCH3 downstream target gene, is expressed consistently with NOTCH3. HEYL knockdown in meniscus cells attenuated the COL1A1 upregulation by CTGF and TGF-𝜷 stimulation. Thus, this study discovers the existence of smooth muscle cells and fibers in the meniscus. Inhibition of NOTCH3 signaling in meniscus smooth muscle cells in a HEYL-dependent manner prevented meniscus fibrosis and exacerbated degeneration. Therefore, NOTCH3/HEYL signaling might be a potential therapeutic target for meniscus fibrosis.

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Section: Resultsmentioning

confidence: 99%

Silencing of NOTCH3 Signaling in Meniscus Smooth Muscle Cells Inhibits Fibrosis and Exacerbates Degeneration in a HEYL‐Dependent Manner

et al. 2023

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“…We quantified renal CaMK4 mRNA levels and found a 6.4-fold increase in CaMK4/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) of Pkd1 RC/RC mice compared with Pkd1 RC/+ littermates ( Figure 1H and I ). Pkd1 RC/RC :Pkd2 +/ – mice have a more rapid onset and severe disease progression of PKD ( Radadiya et al, 2021 ). We found a 7.4-fold elevation of renal CaMK4 mRNA level in 20-week-old Pkd1 RC/RC :Pkd2 +/ – mice compared with the phenotypic normal Pkd1 RC/+ :Pkd2 +/+ mice ( Figure 1J and K ).…”

Section: Resultsmentioning

confidence: 99%

CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation

Zhang

Daniel

Metcalf

et al. 2022

Journal of Molecular Cell Biology

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of fluid-filled cysts causing nephron loss and a decline in renal function. Mammalian target of rapamycin (mTOR) is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement; however, the mechanism for mTOR stimulation remains unclear. We discovered that calcium/calmodulin-dependent kinase IV (CaMK4), a multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and polycystic kidney disease (PKD) mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited cell proliferation and in vitro cyst formation of ADPKD cells. Moreover, inhibition of calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) and calmodulin (CaM), two key upstream regulators of CaMK4, also decreased mTOR signaling. The effects of KN-93 were independent of the LKB1–AMPK pathway and the combination of KN-93 and metformin, an AMPK activator, had additive inhibitory effects on mTOR signaling and in vitro cyst growth. Our data suggest that increased CaMK4 expression and activity contribute to mTOR signaling and proliferation of cystic cells of ADPKD kidneys.

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“…Similar to OKCs, upregulated Notch signaling was found to be important for cyst formation and growth in ADPKD [ 70 ]. According to a recent study, Quinomycin A not only inhibited Notch signaling; at the same time, it targeted HIF-1α, strongly suggesting the crosstalk between HIF-1α and Notch signaling [ 71 ]. It is also speculated that the inhibition of Notch signaling shortens primary cilia, which may result in better patient prognosis as elongated primary cilia were associated with ADPKD [ 70 ].…”

Section: The Role Of Hif-1α Notch and Caspase-3 In The Odontogenic Cy...mentioning

confidence: 99%

Primary cilia and hypoxia-associated signaling in developmental odontogenic cysts in relation to autosomal dominant polycystic kidney disease – A novel insight

Szaraz,

Danek,

Lipovy

et al. 2023

Heliyon

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Quinomycin A reduces cyst progression in polycystic kidney disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 5 publications

References 46 publications

Silencing of NOTCH3 Signaling in Meniscus Smooth Muscle Cells Inhibits Fibrosis and Exacerbates Degeneration in a HEYL‐Dependent Manner

Silencing of NOTCH3 Signaling in Meniscus Smooth Muscle Cells Inhibits Fibrosis and Exacerbates Degeneration in a HEYL‐Dependent Manner

CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation

Primary cilia and hypoxia-associated signaling in developmental odontogenic cysts in relation to autosomal dominant polycystic kidney disease – A novel insight

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