scholarly journals Discerning the role of mechanosensors in regulating proximal tubule function

2016 ◽  
Vol 310 (1) ◽  
pp. F1-F5 ◽  
Author(s):  
Venkatesan Raghavan ◽  
Ora A. Weisz
Keyword(s):  
Shear Stress ◽  
Proximal Tubule ◽  
Primary Cilia ◽  
The Body ◽  
Flow Sensors ◽  
Body Experience ◽  
Flow Sensing ◽  
Axial Shear ◽  
Stretch Activated Channels

All cells in the body experience external mechanical forces such as shear stress and stretch. These forces are sensed by specialized structures in the cell known as mechanosensors. Cells lining the proximal tubule (PT) of the kidney are continuously exposed to variations in flow rates of the glomerular ultrafiltrate, which manifest as changes in axial shear stress and radial stretch. Studies suggest that these cells respond acutely to variations in flow by modulating their ion transport and endocytic functions to maintain glomerulotubular balance. Conceptually, changes in the axial shear stress in the PT could be sensed by three known structures, namely, the microvilli, the glycocalyx, and primary cilia. The orthogonal component of the force produced by flow exhibits as radial stretch and can cause expansion of the tubule. Forces of stretch are transduced by integrins, by stretch-activated channels, and by cell-cell contacts. This review summarizes our current understanding of flow sensing in PT epithelia, discusses challenges in dissecting the role of individual flow sensors in the mechanosensitive responses, and identifies potential areas of opportunity for new study.

Abstract 011: An Orally Absorbable Potent NHE3 Inhibitor Attenuates Angiotensin II-induced Hypertension Primarily by Inhibiting NHE3 in the Proximal Tubule of the Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Hoang Nguyen ◽  
Jia L Zhuo
Keyword(s):  
Proximal Tubule ◽  
The Body ◽  
High Salt ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Small Intestines ◽  
Orally Active ◽  
Nhe3 Inhibitor

We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global ( Nhe3 -/- ) and Nhe3 -/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tg Nhe3 -/- ), suggesting an important role of NHE3 in the development of ANG II-dependent hypertension. In this study, we specifically tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubules of the kidney attenuates ANG II-dependent hypertension induced by a low and slow pressor dose of ANG II supplemented with a high salt diet. Overall, 9 groups (n=5-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via minipump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase systolic blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116 ± 2 mmHg to 140 ± 2 mmHg ( p <0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147 ± 4 mmHg ( p <0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125 ± 4 mmHg in ANG II-infused mice ( p <0.01), and to 134 ± 6 mmHg in ANG II-infused mice supplemented with 2% NaCl ( p <0.01), respectively. Further treatment with AVE0657 and losartan, an AT 1 receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115 ± 5 mmHg, p <0.01). In the kidney, AVE0657 significantly increased 24h urinary Na + excretion from 157.1 ± 6.7 to 207.7 ± 8.1 μmol/24h ( p <0.01) without altering 24h urine excretion or SBP. Furthermore, AVE0657 did not significantly alter 24 h fecal Na + excretion in non ANG II-infused (4.99 ± 0.37 μmol/24h, n.s.) or ANG II-infused mice (4.19 ± 0.67 μmol/24h, n.s.), compared with control (4.02 ± 0.20 μmol/24h, n.s. ) or global Nhe3 -/- mice (50.8 ± 0.8 μmol/24h, p <0.01). Since small intestines in the gut and the proximal tubules of the kidney express the vast majority of NHE3 in the body, these results provide preclinical evidence and perspectives that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to prevent and treat hypertension induced by ANG II and a high salt, mainly by inhibiting NHE3 in the proximal tubule of the kidney.

scholarly journals Biophysics and biofluid dynamics of primary cilia: evidence for and against the flow-sensing function

2017 ◽  
Vol 313 (3) ◽  
pp. F706-F720 ◽  
Author(s):  
Subhra Nag ◽  
Andrew Resnick
Keyword(s):  
Primary Cilia ◽  
Mechanical Response ◽  
Hydrodynamic Drag ◽  
Essential Information ◽  
Biofluid Dynamics ◽  
Flow Sensing ◽  
Experimental Approaches ◽  
Relevant Work ◽  
Cell Signaling Pathways

Primary cilia have been called “the forgotten organelle” for over 20 yr. As cilia now have their own journal and several books devoted to their study, perhaps it is time to reconsider the moniker “forgotten organelle.” In fact, during the drafting of this review, 12 relevant publications have been issued; we therefore apologize in advance for any relevant work we inadvertently omitted. What purpose is yet another ciliary review? The primary goal of this review is to specifically examine the evidence for and against the hypothesized flow-sensing function of primary cilia expressed by differentiated epithelia within a kidney tubule, bringing together differing disciplines and their respective conceptual and experimental approaches. We will show that understanding the biophysics/biomechanics of primary cilia provides essential information for understanding any potential role of ciliary function in disease. We will summarize experimental and mathematical models used to characterize renal fluid flow and incident force on primary cilia and to characterize the mechanical response of cilia to an externally applied force and discuss possible ciliary-mediated cell signaling pathways triggered by flow. Throughout, we stress the importance of separating the effects of fluid shear and stretch from the action of hydrodynamic drag.

TGF-  Signaling in Endothelial-to-Mesenchymal Transition: The Role of Shear Stress and Primary Cilia

2012 ◽  
Vol 5 (212) ◽  
pp. pt2-pt2 ◽  
Author(s):  
P. ten Dijke ◽  
A. D. Egorova ◽  
M.-J. T. H. Goumans ◽  
R. E. Poelmann ◽  
B. P. Hierck
Keyword(s):  
Shear Stress ◽  
Primary Cilia ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

scholarly journals The Mechanosensory Role of Primary Cilia in Vascular Hypertension

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Surya M. Nauli ◽  
Xingjian Jin ◽  
Beerend P. Hierck
Keyword(s):  
Shear Stress ◽  
Primary Cilia ◽  
Fluid Shear Stress ◽  
Vascular System ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Cellular Functions ◽  
Continuous Problem

Local regulation of vascular tone plays an important role in cardiovascular control of blood pressure. Aside from chemical or hormonal regulations, this local homeostasis is highly regulated by fluid-shear stress. It was previously unclear how vascular endothelial cells were able to sense fluid-shear stress. The cellular functions of mechanosensory cilia within vascular system have emerged recently. In particular, hypertension is insidious and remains a continuous problem that evolves during the course of polycystic kidney disease (PKD). The basic and clinical perspectives on primary cilia are discussed with regard to the pathogenesis of hypertension in PKD.

A radical phenomenology of the body: subjectivity and sensations in body image and body schema

2021 ◽  
pp. 52-68
Author(s):  
Helena De Preester
Keyword(s):  
Body Image ◽  
Sensory Input ◽  
Body Schema ◽  
The Body ◽  
Traditional View ◽  
Body Experience ◽  
Bodily Experience ◽  
Body Representations ◽  
Phenomenology Of The Body

The role of sensations for body experience and body representations such as body image and body schema seems indisputable. This chapter discusses the link between sensory input, the experience of one’s own body, and body representations such as body image and body schema. That happens on the basis of Michel Henry’s radical phenomenology of the body, which unites body and subjectivity and reconsiders the role of sensory input for the experience of the body and related representations. Without supporting, but inspired by, Henry’s ontological dualism between subjective and objective body, it is argued that the traditional view that considers sensory signals as all-important for bodily experience misses out a bodily dimension crucial for subjectivity—the body’s subjective dimension, not reigned by current sensory input. Cognitive science seems willing to accept representations that are over and above sensory input but still experiential in nature. The exact status of these ‘offline’ representations is, however, unclear. If it is true that these offline representations are responsible for crucial aspects of bodily subjective life (e.g., unity, ownership, presence), then it is unclear how these representations bring this experience about. Whereas online bodily representations are based on sensory input, offline bodily representations seem to be based on bodily experience over and above sensory life. In other words, they seem to represent or mediate what they are supposed to explain—the subjective body.

scholarly journals Angiotensin-(1-7) and Its Effects in the Kidney

2009 ◽  
Vol 9 ◽  
pp. 522-535 ◽  
Author(s):  
Marc Dilauro ◽  
Kevin D. Burns
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Mesangial Cells ◽  
Gene Knockout ◽  
Collecting Duct ◽  
Tyrosine Phosphatase ◽  
The Body ◽  
Ang Ii

Angiotensin-(1-7) (Ang-[1-7]) is a heptapeptide member of the renin-angiotensin system (RAS), and acts as a vasodilator and antagonist of angiotensin II (Ang II) in the vasculature. The role of Ang-(1-7) in regulating kidney function is not well understood. Within the kidneys, Ang-(1-7) is generated by angiotensin-converting enzyme 2 (ACE2)–mediated degradation of Ang II, sequential cleavage of the precursor angiotensin I (Ang I) by ACE2 and ACE, or the actions of brush-border membrane peptidases on Ang I. Ang-(1-7) mediates its effects via binding to kidney Mas receptors, although some actions may occur via Ang II AT1or AT2receptors.In vitrostudies suggest that Ang-(1-7) is an intrarenal vasodilator. Ang-(1-7) has been reported to induce either natriuresis/diuresis or sodium and water retention, via modulation of sodium transporters in the proximal tubule and loop of Henle, and collecting duct water transport. In the proximal tubule, Ang-(1-7) antagonizes growth-promoting signaling pathways via activation of a protein tyrosine phosphatase, whereas in mesangial cells, Ang-(1-7) stimulates cell growth via activation of mitogen-activated protein kinases. The phenotype of the Mas gene knockout mouse suggests that Ang-(1-7)–signaling events exert cardiovascular protection by regulating blood pressure, and by limiting production of reactive oxygen species and extracellular matrix proteins. Ang-(1-7) also protects against renal injury in the renal wrap hypertension model, independent of effects on blood pressure. In diabetic nephropathy, however, the role of Ang-(1-7) on disease progression remains unclear. In summary, Ang-(1-7) and its receptor Mas have emerged as important components of the intrarenal RAS. The signaling and downstream effects of Ang-(1-7) in the kidney are complex and appear to be cell specific. The body of evidence suggests that Ang-(1-7) is protective against endothelial dysfunction or Ang II–stimulated proximal tubular injury, although the overall effects on glomerular function require further study.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

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