Научная статья на тему 'Regulation of the renal NaCl cotransporter activity by the Wnk kinases signaling network'

Regulation of the renal NaCl cotransporter activity by the Wnk kinases signaling network Текст научной статьи по специальности «Биотехнологии в медицине»

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Аннотация научной статьи по биотехнологиям в медицине, автор научной работы — Gamba G., Hadchouel J., Ellison D. H.

The renal NaCl cotransporter NCC is the major salt transport pathway in the distal convoluted tubule of the mammalian nephron. NCC plays a key role in the regulation of arterial blood pressure. Inhibition of NCC with thiazide type diuretics is one of the cornerstones for the treatment of arterial hypertension. Inactivating mutations of NCC in the Gitelman disease results in arterial hypotension accompanied by hypokalemic metabolic alkalosis. In contrast, increased activity of NCC in the Familial Hyperkalemic Hypertension syndrome (FHH), also known as pseudohypoaldosteronism type II, results in hypertension with hyperkalemic metabolic acidosis. Increased activity of NCC in FHHt is the consequence of mutations in regulatory proteins. Four genes have been demonstrated to produce FHHt: two with no lysine kinases, WNK1 and WNK4, and two proteins known as Kelch-3 and Cul3 that together form a RING-type ubiquitin ligase complex. Recent studies suggest that WNK1 and WNK4 are the targets for Kelch-3/Cul3 ubiquitylation system and thus, FHHt due to mutations in Kelch3/Cul3 produce the disease by affecting the expression of WNK1 and WNK4. The mechanisms involved in the regulation of NCC by WNKs are thus a very important pathway to be defined. Initial studies using in vitro systems and in vivo transgenic mice models suggested that WNK4 is an inhibitor of NCC and that FHHt mutations in WNK4 prevent this inhibition. The model localize WNK1 upstream of WNK4 suggesting that WNK1 inhibits the activity of WNK4 and thus, increased expression of WNK1 in FHHt produces the disease by preventing WNK4 inhibition of NCC. Recent studies in our laboratory provided us with data in both, in vitro and in vivo systems, to propose a different model: WNK1 and WNK3 are potent activators of NCC, and WNK4 is an inhibitor of WNK1/WNK3. This last effect if prevented by angiotensin II, providing a working model to explain, at lest in part, the angiotensin II induced arterial hypertension.

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Текст научной работы на тему «Regulation of the renal NaCl cotransporter activity by the Wnk kinases signaling network»

Abstracts

REGULATION OF THE RENAL NACL COTRANSPORTER ACTIVITY BY THE WNK KINASES SIGNALING NETWORK

Gamba, G.1, Hadchouel, J.2, and Ellison, D.H.3

1 Molecular Physiology Unit. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México

2 INSERM UMR970 - Paris Cardiovascular Research Center and University Paris-Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France

3 Division of Nephrology & Hypertension, Oregon Health & Science University, Portland, Oregon, USA

The renal NaCl cotransporter NCC is the major salt transport pathway in the distal convoluted tubule of the mammalian nephron. NCC plays a key role in the regulation of arterial blood pressure. Inhibition of NCC with thiazide type diuretics is one of the cornerstones for the treatment of arterial hypertension. Inactivating mutations of NCC in the Gitelman disease results in arterial hypotension accompanied by hypokalemic metabolic alkalosis. In contrast, increased activity of NCC in the Familial Hyperkalemic Hypertension syndrome (FHH), also known as pseudohypoaldosteronism type II, results in hypertension with hyperkalemic metabolic acidosis. Increased activity of NCC in FHHt is the consequence of mutations in regulatory proteins. Four genes have been demonstrated to produce FHHt: two with no lysine kinases, WNK1 and WNK4, and two proteins known as Kelch-3 and Cul3 that together form a RING-type ubiquitin ligase complex. Recent studies suggest that WNK1 and WNK4 are the targets for

Kelch-3/Cul3 ubiquitylation system and thus, FHHt due to mutations in Kelch3/Cul3 produce the disease by affecting the expression of WNK1 and WNK4. The mechanisms involved in the regulation of NCC by WNKs are thus a very important pathway to be defined. Initial studies using in vitro systems and in vivo transgenic mice models suggested that WNK4 is an inhibitor of NCC and that FHHt mutations in WNK4 prevent this inhibition. The model localize WNK1 upstream of WNK4 suggesting that WNK1 inhibits the activity of WNK4 and thus, increased expression of WNK1 in FHHt produces the disease by preventing WNK4 inhibition of NCC. Recent studies in our laboratory provided us with data in both, in vitro and in vivo systems, to propose a different model: WNK1 and WNK3 are potent activators of NCC, and WNK4 is an inhibitor of WNK1/WNK3. This last effect if prevented by angiotensin II, providing a working model to explain, at lest in part, the angiotensin II induced arterial hypertension.

RECENT PROGRESS IN SINGLE-CELL VOLUME MEASUREMENT TECHNIQUES Grygorczyk, R.1 and Orlov, S.N.1'2

1 Research Center, University of Montreal Hospital, Montreal, Canada

2 Laboratory of Physical Chemistry of Biological Membranes, M.V. Lomonosov Moscow State University, Moscow, Russian Federation

Accurate measurements of rapid cell volume changes in response to different stimuli are essential in the studies examining many aspects of cell physiology and pathology, including cell volume sensor identification. Several technique are used to measure cell volume, including Coulter counter, fluorescent techniques, electronic impedance, and video microscopy. More recent approaches to cell volume measurements utilize atomic force microscopy, ion conductance microscopy, or fluid flow in a rigid system. Each of these techniques has strengths and limitations, differing in accuracy, temporal resolution and applicability to spe-

cifically-prepared cells. For example, the Coulter counter technique can rapidly measure cell volume of large cell population, but it can only be used with floating, ideally almost perfectly spherical cells. Here, we will briefly review and compare different currently-available cell volume measurement techniques, focusing on recently developed light microscopy techniques, especially those capable of measuring absolute cell volume in real-time, providing full 3D information on cell shape, and those that could be applied to substrate-attached cells.

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Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24-68

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