Calcium-mediated mechanisms of cystic expansion

Abdul-Majeed, Shakila; Nauli, Surya M.

doi:10.1016/j.bbadis.2010.09.016

Cited by 30 publications

(28 citation statements)

References 104 publications

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“…Primary cilium functions as a sensory organelle and houses a large number of specialized proteins. These specialized proteins are involved in various sensing of fluidshear stress, chemical, photon, gravity, and many others, which function may be dependent or independent from extracellular calcium influx [2,17]. Most importantly, these sensory proteins are not synthesized within the ciliary body.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms regulating cilia growth and cilia function in endothelial cells

Abdul-Majeed

Moloney

Nauli

2011

Cell. Mol. Life Sci.

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The primary cilium is an important sensory organelle present in most mammalian cells. Our current studies aim at examining intracellular molecules that regulate cilia length and/or cilia function in vitro and ex vivo. For the first time, we show that intracellular cAMP and cAMP-dependent protein kinase (PKA) regulate both cilia length and function in vascular endothelial cells. Although calcium-dependent protein kinase modulates cilia length, it does not play a significant role in cilia function. Cilia length regulation also involves mitogen-activated protein kinase (MAPK), protein phosphatase-1 (PP-1), and cofilin. Furthermore, cofilin regulates cilia length through actin rearrangement. Overall, our study suggests that the molecular interactions between cilia function and length can be independent of one another. Although PKA regulates both cilia length and function, changes in cilia length by MAPK, PP-1, or cofilin do not have a direct correlation to changes in cilia function. We propose that cilia length and function are regulated by distinct, yet complex intertwined signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Mechanisms regulating cilia growth and cilia function in endothelial cells

Abdul-Majeed

Moloney

Nauli

2011

Cell. Mol. Life Sci.

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“…In addition, for each experimental study, equal numbers of rats in the vitamin D-deficient and -sufficient groups received the same batch of a diet at any one time. Because intacellular calcium signaling is altered in PKD (1,43) and as there are no previous published data in PKD, both the vitamin D-sufficient and -deficient diets contained the same amount of calcium (0.5%). Food intake was monitored daily at 0900 by weighing the pellets remaining in the food hoppers at the end of a 24-h period.…”

Section: Experimental Diets and Monitoring Of Food Intakementioning

confidence: 99%

Chronic effects of dietary vitamin D deficiency without increased calcium supplementation on the progression of experimental polycystic kidney disease

Rangan

Schwensen

Foster

et al. 2013

American Journal of Physiology-Renal Physiology

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Increasing evidence indicates that vitamin D deficiency exacerbates chronic kidney injury, but its effects on renal enlargement in polycystic kidney disease (PKD) are not known. In this study, male Lewis polycystic kidney disease (LPK) rats received a normal diet (ND; AIN-93G) supplemented with or without cholecalciferol (vitamin D-deficient diet, VDD; both 0.5% calcium), commenced at either postnatal week 3 (until weeks 10-20; study 1) or from week 10 (until week 20; study 2). Levels of 25-hydroxy vitamin D were reduced in groups receiving the VDD (12 ± 1 nmol/l vs. 116 ± 5 in ND; P < 0.001). In study 1, food intake and weight gain increased by ∼25% in LPK rats receiving the VDD ad libitum, and at week 20 this was associated with a mild reduction in the corrected serum calcium (SCa(2+), 7.4%) and TKW:BW ratio (8.8%), and exacerbation of proteinuria (87%) and hypertension (19%; all P < 0.05 vs. ND). When LPK rats were pair-fed for weeks 3-10, there was a further reduction in the SCa(2+) (25%) and TKW:BW ratio (22%) in the VDD group (P < 0.05 vs. ND). In study 2, the VDD did not alter food intake and body weight, reduced SCa(2+) (7.7%), worsened proteinuria (41.9%), interstitial monocyte accumulation (26.4%), renal dysfunction (21.4%), and cardiac enlargement (13.2%, all P < 0.05), but there was a trend for a reduction in the TKW:BW ratio (13%, P = 0.09). These data suggest that chronic vitamin D deficiency has adverse long-term actions on proteinuria, interstitial inflammation, renal function, and cardiovascular disease in PKD, and these negate its mild inhibitory effect on kidney enlargement.

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“…1,14 Our results indicate that PI3K-C2a modulates trafficking of primary cilium-bound cargo proteins such as polycystin-2, thus allowing polycystin-mediated control of proliferative signals in kidney tubular cells. This function is strictly dose-dependent and a 50% reduction in PI3K-C2a expression is sufficient to cause primary cilium abnormalities in kidney tubules as well as to predispose to renal cyst formation.…”

Section: Discussionmentioning

confidence: 92%

“…12 Polycystin-evoked calcium in turn is proposed to regulate cell polarity and to activate intracellular pathways that counteract proliferation signals, such as the mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, eventually avoiding cystogenesis. 14 Transport of polycystins to the primary cilium is tightly regulated and several mediators of different trafficking steps have been identified to direct vesicles to the primary cilium base. 3,[15][16][17] In this region, known as basal body, a selective barrier regulates entry of specific proteins inside the ciliary compartment.…”

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confidence: 99%

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

Franco

Margaria

Santis

et al. 2016

Journal of the American Society of Nephrology

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Signaling from the primary cilium regulates kidney tubule development and cyst formation. However, the mechanism controlling targeting of ciliary components necessary for cilium morphogenesis and signaling is largely unknown. Here, we studied the function of class II phosphoinositide 3-kinase-C2a (PI3K-C2a) in renal tubule-derived inner medullary collecting duct 3 cells and show that PI3K-C2a resides at the recycling endosome compartment in proximity to the primary cilium base. In this subcellular location, PI3K-C2a controlled the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. Consistently, partial reduction of PI3K-C2a was sufficient to impair elongation of the cilium and the ciliary transport of polycystin-2, as well as to alter proliferation signals linked to polycystin activity. In agreement, heterozygous deletion of PI3K-C2a in mice induced cilium elongation defects in kidney tubules and predisposed animals to cyst development, either in genetic models of polycystin-1/2 reduction or in response to ischemia/reperfusion-induced renal damage. These results indicate that PI3K-C2a is required for the transport of ciliary components such as polycystin-2, and partial loss of this enzyme is sufficient to exacerbate the pathogenesis of cystic kidney disease.

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Calcium-mediated mechanisms of cystic expansion

Cited by 30 publications

References 104 publications

Mechanisms regulating cilia growth and cilia function in endothelial cells

Mechanisms regulating cilia growth and cilia function in endothelial cells

Chronic effects of dietary vitamin D deficiency without increased calcium supplementation on the progression of experimental polycystic kidney disease

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

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