The Mechanosensory Role of Primary Cilia in Vascular Hypertension

Nauli, Surya M.; Jin, Xingjian; Hierck, Beerend P.

doi:10.1155/2011/376281

Cited by 37 publications

(45 citation statements)

References 101 publications

(92 reference statements)

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“…Multiple ion channels (22), receptors (e.g., AT 1 R) and organelles (e.g., cilia; Ref. 34 nochemical signal transduction of shear. A number of shear sensors are also redox sensitive (30), which may contribute to shifting the mechanism of dilation, as IILP increases vascular superoxide levels (10).…”

Section: Post Iilp Sepiapterinmentioning

confidence: 99%

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

Beyer

Durand

Hockenberry

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Endothelial nitric oxide (NO) is the primary mediator of flow-mediated dilation (FMD) in human adipose microvessels. Impaired NO-mediated vasodilation occurs after acute and chronic hypertension, possibly due to excess generation of reactive oxygen species (ROS). The direct role of pressure elevation in this impairment of human arteriolar dilation is not known. We tested the hypothesis that elevation in pressure is sufficient to impair FMD. Arterioles were isolated from human adipose tissue and cannulated, and vasodilation to graded flow gradients was measured before and after exposure to increased intraluminal pressure (IILP; 150 mmHg, 30 min). The mediator of FMD was determined using pharmacological agents to reduce NO [N(G)-nitro-l-arginine methyl ester (l-NAME), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)], or H2O2 [polyethylene glycol (PEG)-catalase], and mitochondrial (mt) ROS was quantified using fluorescence microscopy. Exposure to IILP decreased overall FMD (max %dilation: 82.7 ± 4.9 vs. 62 ± 5.6; P < 0.05). This dilation was abolished by treatment with l-NAME prepressure and PEG-catalase after IILP (max %dilation: l-NAME: 23.8 ± 6.1 vs. 74.8 ± 8.6; PEG-catalase: 71.8 ± 5.9 vs. 24.6 ± 10.6). To examine if this change was mediated by mtROS, FMD responses were measured in the presence of the complex I inhibitor rotenone or the mitochondrial antioxidant mitoTempol. Before IILP, FMD was unaffected by either compound; however, both inhibited dilation after IILP. The fluorescence intensity of mitochondria peroxy yellow 1 (MitoPY1), a mitochondria-specific fluorescent probe for H2O2, increased during flow after IILP (%change from static: 12.3 ± 14.5 vs. 127.9 ± 57.7). These results demonstrate a novel compensatory dilator mechanism in humans that is triggered by IILP, inducing a change in the mediator of FMD from NO to mitochondria-derived H2O2.

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Section: Post Iilp Sepiapterinmentioning

confidence: 99%

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

Beyer

Durand

Hockenberry

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…23 To complicate things further, although hypertension is a hallmark of ADPKD, it is normally associated with only one type of NPHP (infantile) in humans. 58 Our findings in Tmem218 -/-mice suggest that hypertension is not present until creatinine levels are elevated, and the hypertension that we observed is thus most likely a consequence of renal failure. Nevertheless, it is interesting to note that disruptions to the mechanosensory role of primary cilia have recently been proposed as potential contributory causes of vascular hypertension.…”

Section: Hypertensionmentioning

confidence: 48%

Nephronophthisis and Retinal Degeneration inTmem218^–/–Mice

et al. 2014

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Mice deficient in TMEM218 (Tmem218 -/-) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218 -/-mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218 -/-mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218 -/-mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.

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“…[16,17] Furthermore, we also showed that ECs express fibrocystin, a protein that has been implicated in the structure and function of the primary cilia, an organelle that has been associated with regulation in vascular function. [18,19] Taking into account that the main defect in the PCK model, compared to WT, is a splicing mutation in fibrocystin with potential defect in their structure and function,[13] this defect in primary cilia may in part account for the vascular abnormalities described. Whether there are other cilia abnormalities in this model and if they are related to the impaired vasoreactivity observed in this study is still unclear and further studies are needed.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Dysfunction Occurs prior to Clinical Evidence of Polycystic Kidney Disease

et al. 2013

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Objective: Polycystic kidney disease (PKD), a monogenic disease with an autosomal dominant or an autosomal recessive form of inheritance (ARPKD), is the most common genetic cause of renal dysfunction and end-stage renal failure. In addition to the development of cysts, the autosomal form of PKD is associated with vascular endothelial dysfunction, a marker of vascular disease. Whether vascular endothelial dysfunction is also present in ARPKD, and its relationship with renal dysfunction remain to be determined. Methods: ARPKD rats (PCK model) and controls were studied at 6 and 10 weeks of age, and mean arterial pressure and renal function were measured. Aortic endothelial function was assessed using organ chamber techniques. Aortic endothelial cells (ECs) were isolated, characterized and their function studied. Results: Compared to controls, ARPKD animals had a decrease in the vasorelaxation to endothelium-dependent vasodilators, even prior to changes in mean arterial pressure or renal function. The abnormal vasoreactivity was corrected with L-arginine (a precursor of nitric oxide, NO), while the expression of endothelial NO synthase (eNOS) was unchanged. Furthermore, isolated ECs from 6-week-old ARPKD animals showed increased oxidative stress, with preserved eNOS expression and abnormal patterns of migration and angiogenic capacity (measured by the scratch and tube formation assays, respectively). Conclusion: ARPKD leads to impairments in aortic vascular function and ECs at an early stage, which can have significant functional consequences, potentially representing a novel therapeutic target in this disease.

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The Mechanosensory Role of Primary Cilia in Vascular Hypertension

Cited by 37 publications

References 101 publications

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

Nephronophthisis and Retinal Degeneration inTmem218^–/–Mice

Endothelial Dysfunction Occurs prior to Clinical Evidence of Polycystic Kidney Disease

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The Mechanosensory Role of Primary Cilia in Vascular Hypertension

Cited by 37 publications

References 101 publications

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles

Nephronophthisis and Retinal Degeneration inTmem218–/–Mice

Endothelial Dysfunction Occurs prior to Clinical Evidence of Polycystic Kidney Disease

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Nephronophthisis and Retinal Degeneration inTmem218^–/–Mice