Divergent function of polycystin 1 and polycystin 2 in cell size regulation

Viau, Amandine; Kotsis, Fruzsina; Boehlke, Christopher; Braeg, Simone; Klein, Marinella; Nitschke, Roland; Walz, Gerd; Kuehn, E. Wolfgang

doi:10.1016/j.bbrc.2019.10.074

Cited by 12 publications

(11 citation statements)

References 27 publications

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“…We show that the EC area regulation appears to work via cilia-mediated flow sensing, while the EC extrusion regulation may rely on cilia-independent mechanosensitivity mediated by the TRP channel pkd2. This view is consistent with recent findings demonstrating divergent functions for Pkd proteins, in which kidney cell size regulation in response to cilia-mediated flow sensing requires pkd1 but not pkd2 (Boehlke et al, 2010;Viau et al, 2019). Overall, our work indicates that the cellular machinery that controls EC shape and size is in part modulated by mechanical forces in vivo.…”

Section: Discussionsupporting

confidence: 93%

Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta

et al. 2020

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Section: Discussionsupporting

confidence: 93%

Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta

et al. 2020

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“…Direct evidence showing PC-1 or PC-2 controls mTORC1 in a cilium-dependent manner under physiological conditions remains scarce. A recent study from Kuehn’s group provides the first evidence showing a direct impact of PC-1 on mTORC1 activity [ 83 ]. It was found that flow stress-induced mTORC1 downregulation required PC-1, but not PC-2.…”

Section: Regulation Of Mtorc1 By Polycystin-1mentioning

confidence: 99%

Reciprocal Regulation between Primary Cilia and mTORC1

Lai

Jiang

2020

Genes

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In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in restricting mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for quiescent cells to maintain their quiescence. Multiple mechanisms have been identified that mediate the inhibitory effect of primary cilia on mTORC1 signaling. These mechanisms depend on several tumor suppressor proteins localized within the ciliary compartment, including liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), polycystin-1, and polycystin-2. Conversely, changes in mTORC1 activity are able to affect ciliogenesis and stability indirectly through autophagy. In this review, we summarize recent advances in our understanding of the reciprocal regulation of mTORC1 and primary cilia.

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“…In the ADPKD state, the 30 kilodalton (kDa) cytoplasmic (C) tail of polycystin-1 is released into the cytoplasm after cleavage and translocate to the nucleus where it interacts with the transcriptional co-activator P100 and STAT6 and co activates the STAT6. The remaining membrane-anchored portion (15 kDa) of polycystin-1 inhibits the STAT6 as it loses the ability to activate STAT6 (Ma et al 2005 ) …”

Section: Pathophysiologymentioning

confidence: 99%

“…MEK phosphorylates the extracellular signal-regulated kinase (ERK); also known as mitogen-activated protein kinase (MAPK) which further phosphorylates several other proteins that regulate cell proliferation, and differentiation. Decreased polycystin-1 expression lowers the activation threshold of the MAPK/ ERK pathway by IGF-1 and increased EGF-induced inward currents in kidney epithelial cell lines are produced due to over-expression of polycystin-2; together lead cystogenesis (Ma et al 2005 ; Parker et al 2007 ) …”

Section: Pathophysiologymentioning

confidence: 99%

“…This genetic disorder has affected around 12.5 million people worldwide regardless of sex and ethnicity and is the fourth leading cause for about 10% of patients with ESRD owing to which, it poses a considerable economic burden of approximately $10 billion (Nowak et al 2018 ; Chapman et al 2015 ). Although the exact mechanism behind cystogenesis is incompletely understood, a significant number of studies have attributed it to the alterations of different molecular signaling pathways that are regulated by genetic products of PKD1 and PKD2 that is polycystin-1 and polycystin-2, respectively found in primary cilia (Viau et al 2020 ). ADPKD is incurable, and the treatment of ADPKD is limited to the management of different renal and extra-renal complications.…”

Section: Introductionmentioning

confidence: 99%

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Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects

Saini¹,

Saini²,

Singh

2020

Mol Med

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Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.

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Divergent function of polycystin 1 and polycystin 2 in cell size regulation

Cited by 12 publications

References 27 publications

Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta

Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta

Reciprocal Regulation between Primary Cilia and mTORC1

Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects

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