Luciana Morla | UPMC Sorbonne Universités (original) (raw)

Papers by Luciana Morla

bioRxiv, 2021

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leadin... more Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leading to oedema. This Na retention is usually attributed to epithelial sodium channel (ENaC) activation following plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We, then, identified a truncated variant of acid sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when co-expressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that expression of the truncated ASIC2b in kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but in any of ...

Paracrine communication between different parts of the renal tubule is increasingly recognized as... more Paracrine communication between different parts of the renal tubule is increasingly recognized as an important determinant of renal function. Previous studies have shown that changes in dietary acid-base load can reverse the direction of apical-ketoglutarate (KG) transport in the proximal tubule and Henle's loop from reabsorption (acid load) to secretion (base load). Here we show that the resulting changes in the luminal concentrations of KG are sensed by the KG receptor OXGR1 expressed in the type B and non-A-non-B intercalated cells of the connecting tubule (CNT) and the cortical collecting duct (CCD). The addition of 1 mM KG to the tubular lumen strongly stimulated Cl(-)-dependent HCO(3)(-) secretion and electroneutral transepithelial NaCl reabsorption in microperfused CCDs of wild-type mice but not Oxgr1(-/-) mice. Analysis of alkali-loaded mice revealed a significantly reduced ability of Oxgr1(-/-) mice to maintain acid-base balance. Collectively, these results demonstrate that OXGR1 is involved in the adaptive regulation of HCO(3)(-) secretion and NaCl reabsorption in the CNT/CCD under acid-base stress and establish KG as a paracrine mediator involved in the functional coordination of the proximal and the distal parts of the renal tubule.

Les recepteurs actives par les proteases de type 2 (PAR2) sont des recepteurs couples aux protein... more Les recepteurs actives par les proteases de type 2 (PAR2) sont des recepteurs couples aux proteines G trimeriques dont la particularite est d’etre actives par clivage proteolytique de leur domaine N-terminal extracellulaire par des serines proteases. Nous avons etudie le role de PAR2 dans le transport ionique dans deux segments du tubule renal participant a la regulation fine de la balance du sodium et du potassium. Dans la branche large ascendante corticale de l’anse de Henle, nous avons montre que l’activation de PAR2 induit une augmentation de la reabsorption transcellulaire et paracellulaire de NaCl en stimulant la Na,K-ATPase et en augmentant la permeabilite paracellulaire au Na+. Dans le canal collecteur cortical, PAR2 est exprime dans les cellules principales et les cellules intercalaires. Dans les premieres, l’activation de PAR2 induit une faible activation de la reabsorption de Na+ via le canal ENaC et une inhibition de la secretion de K+ via le canal ROMK. Dans les seconde...

Néphrologie & Thérapeutique, 2015

Introduction Le recepteur active par les proteases de type 2 (PAR2) induit une augmentation rapid... more Introduction Le recepteur active par les proteases de type 2 (PAR2) induit une augmentation rapide de la reabsorption de sodium dans le canal collecteur cortical (CCD). De plus, l’activation precoce de PAR2 lors d’une carence sodee est necessaire au maintien de la pression arterielle chez la souris [1] . Notre objectif est de determiner quelle protease active PAR2 dans le CCD en reponse a une carence sodee. La matriptase, connue pour activer PAR2 in vivo dans l’ectoderme est exprimee a la membrane des CCD chez l’homme [2] . Nous avons recherche : – si la matriptase est exprimee dans le nephron de souris ; – si elle active PAR2 dans des CCD microperfuses in vitro ; – si elle est activee dans les CCD de souris carencees en sodium. Materiels et methodes Les ARNm de la matriptase ont ete quantifies par RT-qPCR dans les differents segments du nephron de souris normales et dans des CCD de souris carencees en sodium. Le flux net de sodium dans des CCD de souris normales ou PAR2-/- a ete determine par microperfusion in vitro, dans des conditions basales ou apres 15 min d’exposition a un milieu peritubulaire acide (pH = 6) connu pour activer la matriptase. Resultats La matriptase est plus fortement exprimee dans le nephron distal de souris que dans le nephron proximal. Son expression dans le CCD est significativement augmentee apres 2 jours de carence sodee. In vitro, l’acidification du milieu peritubulaire induit une reabsorption de sodium dans le CCD des souris normales mais pas dans le CCD de souris PAR2-/-. Discussion Nos resultats montrent pour la premiere fois que la matriptase, exprimee dans le nephron distal, est induite precocement lors d’une carence sodee. De plus, ils indiquent qu’une diminution du pH peritubulaire induit une augmentation de la reabsorption de sodium dans le CCD de souris de facon dependante de PAR2. La matriptase etant activee a pH acide pourrait etre a l’origine de l’activation de PAR2 dans cette condition. Conclusion La matriptase est un bon candidat en tant qu’activateur de PAR2 dans le CCD et pourrait etre un nouvel acteur dans la regulation de la balance sodee et de la pression arteriel.

JCI Insight, 2021

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention le... more Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention leading to edema. This sodium retention is usually attributed to epithelial sodium channel (ENaC) activation after plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped (CC) rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We then identified a truncated variant of acid-sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when coexpressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that the expression of the truncated ASIC2b in the kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS b...

The Journal of Physiology

American Journal of Physiology-Renal Physiology

Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affec... more Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affect water balance and plasma osmolality. Water homeostasis studies in small animals require the use of invasive or terminal methods that make intracellular and extracellular fluid volume (ICF and ECF) monitoring over time stressful and time consuming. We examined the feasibility of monitoring mice ECF by a non-invasive method, using time-domain nuclear magnetic resonance (TD-NMR). This technique allows differentiating protons in a liquid environment (free fluid) from protons in soft tissues containing a majority of either small molecules (lean) or large molecules (fat). Moreover, this apparatus enables rapid, non-invasive, and repeated measurements on the same animal. We assessed the feasibility of coupling TD-NMR analysis to a longitudinal metabolic cage study by monitoring mice daily. We determined the effect of a 24-hour water deprivation on mice body parameters and detected a sequentia...

American Journal of Physiology-Renal Physiology

We reported recently that type-A intercalated cells of the collecting duct secrete sodium by a me... more We reported recently that type-A intercalated cells of the collecting duct secrete sodium by a mechanism coupling basolateral type-1 Na+/K+/2Cl- cotransporter with apical type-2 H,K-ATPase (HKA2) functioning under its Na+/K+ exchange mode. The first aim of this study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with sodium retention. The second aim of this study was to evaluate whether ANP-induced stimulation of sodium secretion by type-A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In Xenopus oocytes expressing HKA2, cGMP, the second messenger of ANP, increases the membrane expression, the activity and the Na+-transporting rate of HKA2. Feeding mice with a NH4Cl-enriched diet increased urinary excretion of aldosterone and induced a transient sodium retention that reversed within 3 days. At that time, expression of ANP mRNAs...

The Journal of Physiology, 2016

The cortical collecting duct (CCD) plays an essential role in sodium homeostasis by fine-tuning t... more The cortical collecting duct (CCD) plays an essential role in sodium homeostasis by fine-tuning the amount of sodium that is excreted in the urine. r Ex vivo, the microperfused CCD reabsorbs sodium in the absence of lumen-to-bath concentration gradients. r In the present study, we show that, in the presence of physiological lumen-to-bath concentration gradients, and in the absence of endocrine, paracrine and neural regulation, the mouse CCD secretes sodium, which represents a paradigm shift. r This secretion occurs via the paracellular route, as well as a transcellular pathway that is energized by apical H + /K +-ATPase type 2 pumps operating as Na + /K + exchangers. r The newly identified transcellular secretory pathway represents a physiological target for the regulation of sodium handling and for anti-hypertensive therapeutic agents.

World journal of biological chemistry, Jan 26, 2016

The renal handling of Na(+) balance is a major determinant of the blood pressure (BP) level. The ... more The renal handling of Na(+) balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na(+) represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na(+) excretion and are the target of many different regulatory processes that modulate Na(+) retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na(+) absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na(+) excretion, this review ...

The Journal of physiology, Jan 15, 2011

Nephrotic syndrome features massive proteinuria and retention of sodium which promotes ascite for... more Nephrotic syndrome features massive proteinuria and retention of sodium which promotes ascite formation. In the puromycin aminonucleoside-induced rat model of nephrotic syndrome, sodium retention originates from the collecting duct where it generates a driving force for potassium secretion. However, there is no evidence for urinary potassium loss or hypokalaemia in the nephrotic syndrome. We therefore investigated the mechanism preventing urinary potassium loss in the nephrotic rats and, for comparison, in hypovolaemic rats, another model displaying increased sodium reabsorption in collecting ducts. We found that sodium retention is not associated with urinary loss of potassium in either nephrotic or hypovolaemic rats, but that different mechanisms account for potassium conservation in the two models. Collecting ducts from hypovolaemic rats displayed high expression of the potassium-secreting channel ROMK but no driving force for potassium secretion owing to low luminal sodium avail...

Physiological Genomics, 2006

Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in a... more Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in acid or base dietary intake. Because collecting ducts constitute the final site for regulating urine acid-base balance, we undertook to identify the gene network involved in acid-base transport and regulation in the mouse outer medullary collecting duct (OMCD). For this purpose, we combined kidney functional studies and quantitative analysis of gene expression in OMCDs, by transcriptome and candidate gene approaches, during metabolic acidosis. Furthermore, to better delineate the set of genes concerned with acid-base disturbance, the OMCD transcriptome of acidotic mice was compared with that of both normal mice and mice undergoing an adaptative response through potassium depletion. Metabolic acidosis, achieved through an NH4Cl-supplemented diet for 3 days, not only induced acid secretion but also stimulated the aldosterone and vasopressin systems and triggered cell proliferation. Accordin...

Journal of Clinical Investigation, 2010

Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulat... more Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloridesensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na + and Clin mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na +-driven Cl-/HCO 3exchanger (NDCBE/SLC4A8) and the Na +-independent Cl-/HCO 3exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na + reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice. Authorship note: Françoise Leviel and Christian A. Hübner share first authorship.

Journal of Clinical Investigation, 2013

Values are means ± SD. Student's t-test. All urine and blood samples were collected from independ... more Values are means ± SD. Student's t-test. All urine and blood samples were collected from independent mice.

Journal of Biological Chemistry, 2013

Background: The function of proteinase-activated receptor 2 (PAR2) in the distal nephron remains ... more Background: The function of proteinase-activated receptor 2 (PAR2) in the distal nephron remains unknown. Results: PAR2 activation increases electroneutral sodium reabsorption and inhibits potassium secretion in collecting ducts and thereby controls blood pressure and plasma potassium. Conclusion: PAR2 controls sodium and potassium homeostasis. Significance: PAR2 is a new actor of aldosterone paradox but also an aldosterone-independent modulator of blood pressure and plasma potassium.

Journal of Biological Chemistry, 2008

Genes to Cells, 2003

Background : In Drosophila and vertebrates, suppressor of fused (Su(fu)) proteins act as negative... more Background : In Drosophila and vertebrates, suppressor of fused (Su(fu)) proteins act as negative regulators of the Gli / Ci transcription factors, which mediate the transcriptional effects of Hh signalling. Results : We sought for novel partners of Su(fu) in fly using the two-hybrid method. Most of the Su(fu) interactors thus identified are (or are likely to be) able to enter the nucleus. We focused on one of these putative partners, dMLF, which resembles vertebrate myelodysplasia/myeloid leukaemia factors 1 and 2. We demonstrate that dMLF binds specifically to Su(fu) in vitro and in vivo. Using a novel anti-dMLF antibody, we showed, that dMLF is a nuclear, chromosome-associated protein. We overexpressed a dMLF transgene in fly using an inducible expression system and showed that dMLF overexpression disrupts normal development, leading to either a lethal phenotype or adult structural defects associated with apoptosis and increased DNA synthesis. Furthermore, the dMLF-induced eye phenotype is enhanced by the loss of Su(fu) function, suggesting a genetic interaction between Su(fu) and dMLF. Conclusion : We propose that dSu(fu) and dMLF act together at the transcriptional level to coordinate patterning and proliferation during development.

bioRxiv, 2021

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leadin... more Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leading to oedema. This Na retention is usually attributed to epithelial sodium channel (ENaC) activation following plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We, then, identified a truncated variant of acid sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when co-expressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that expression of the truncated ASIC2b in kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but in any of ...

Paracrine communication between different parts of the renal tubule is increasingly recognized as... more Paracrine communication between different parts of the renal tubule is increasingly recognized as an important determinant of renal function. Previous studies have shown that changes in dietary acid-base load can reverse the direction of apical-ketoglutarate (KG) transport in the proximal tubule and Henle's loop from reabsorption (acid load) to secretion (base load). Here we show that the resulting changes in the luminal concentrations of KG are sensed by the KG receptor OXGR1 expressed in the type B and non-A-non-B intercalated cells of the connecting tubule (CNT) and the cortical collecting duct (CCD). The addition of 1 mM KG to the tubular lumen strongly stimulated Cl(-)-dependent HCO(3)(-) secretion and electroneutral transepithelial NaCl reabsorption in microperfused CCDs of wild-type mice but not Oxgr1(-/-) mice. Analysis of alkali-loaded mice revealed a significantly reduced ability of Oxgr1(-/-) mice to maintain acid-base balance. Collectively, these results demonstrate that OXGR1 is involved in the adaptive regulation of HCO(3)(-) secretion and NaCl reabsorption in the CNT/CCD under acid-base stress and establish KG as a paracrine mediator involved in the functional coordination of the proximal and the distal parts of the renal tubule.

Les recepteurs actives par les proteases de type 2 (PAR2) sont des recepteurs couples aux protein... more Les recepteurs actives par les proteases de type 2 (PAR2) sont des recepteurs couples aux proteines G trimeriques dont la particularite est d’etre actives par clivage proteolytique de leur domaine N-terminal extracellulaire par des serines proteases. Nous avons etudie le role de PAR2 dans le transport ionique dans deux segments du tubule renal participant a la regulation fine de la balance du sodium et du potassium. Dans la branche large ascendante corticale de l’anse de Henle, nous avons montre que l’activation de PAR2 induit une augmentation de la reabsorption transcellulaire et paracellulaire de NaCl en stimulant la Na,K-ATPase et en augmentant la permeabilite paracellulaire au Na+. Dans le canal collecteur cortical, PAR2 est exprime dans les cellules principales et les cellules intercalaires. Dans les premieres, l’activation de PAR2 induit une faible activation de la reabsorption de Na+ via le canal ENaC et une inhibition de la secretion de K+ via le canal ROMK. Dans les seconde...

Néphrologie & Thérapeutique, 2015

Introduction Le recepteur active par les proteases de type 2 (PAR2) induit une augmentation rapid... more Introduction Le recepteur active par les proteases de type 2 (PAR2) induit une augmentation rapide de la reabsorption de sodium dans le canal collecteur cortical (CCD). De plus, l’activation precoce de PAR2 lors d’une carence sodee est necessaire au maintien de la pression arterielle chez la souris [1] . Notre objectif est de determiner quelle protease active PAR2 dans le CCD en reponse a une carence sodee. La matriptase, connue pour activer PAR2 in vivo dans l’ectoderme est exprimee a la membrane des CCD chez l’homme [2] . Nous avons recherche : – si la matriptase est exprimee dans le nephron de souris ; – si elle active PAR2 dans des CCD microperfuses in vitro ; – si elle est activee dans les CCD de souris carencees en sodium. Materiels et methodes Les ARNm de la matriptase ont ete quantifies par RT-qPCR dans les differents segments du nephron de souris normales et dans des CCD de souris carencees en sodium. Le flux net de sodium dans des CCD de souris normales ou PAR2-/- a ete determine par microperfusion in vitro, dans des conditions basales ou apres 15 min d’exposition a un milieu peritubulaire acide (pH = 6) connu pour activer la matriptase. Resultats La matriptase est plus fortement exprimee dans le nephron distal de souris que dans le nephron proximal. Son expression dans le CCD est significativement augmentee apres 2 jours de carence sodee. In vitro, l’acidification du milieu peritubulaire induit une reabsorption de sodium dans le CCD des souris normales mais pas dans le CCD de souris PAR2-/-. Discussion Nos resultats montrent pour la premiere fois que la matriptase, exprimee dans le nephron distal, est induite precocement lors d’une carence sodee. De plus, ils indiquent qu’une diminution du pH peritubulaire induit une augmentation de la reabsorption de sodium dans le CCD de souris de facon dependante de PAR2. La matriptase etant activee a pH acide pourrait etre a l’origine de l’activation de PAR2 dans cette condition. Conclusion La matriptase est un bon candidat en tant qu’activateur de PAR2 dans le CCD et pourrait etre un nouvel acteur dans la regulation de la balance sodee et de la pression arteriel.

JCI Insight, 2021

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention le... more Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention leading to edema. This sodium retention is usually attributed to epithelial sodium channel (ENaC) activation after plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped (CC) rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We then identified a truncated variant of acid-sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when coexpressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that the expression of the truncated ASIC2b in the kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS b...

The Journal of Physiology

American Journal of Physiology-Renal Physiology

Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affec... more Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affect water balance and plasma osmolality. Water homeostasis studies in small animals require the use of invasive or terminal methods that make intracellular and extracellular fluid volume (ICF and ECF) monitoring over time stressful and time consuming. We examined the feasibility of monitoring mice ECF by a non-invasive method, using time-domain nuclear magnetic resonance (TD-NMR). This technique allows differentiating protons in a liquid environment (free fluid) from protons in soft tissues containing a majority of either small molecules (lean) or large molecules (fat). Moreover, this apparatus enables rapid, non-invasive, and repeated measurements on the same animal. We assessed the feasibility of coupling TD-NMR analysis to a longitudinal metabolic cage study by monitoring mice daily. We determined the effect of a 24-hour water deprivation on mice body parameters and detected a sequentia...

American Journal of Physiology-Renal Physiology

We reported recently that type-A intercalated cells of the collecting duct secrete sodium by a me... more We reported recently that type-A intercalated cells of the collecting duct secrete sodium by a mechanism coupling basolateral type-1 Na+/K+/2Cl- cotransporter with apical type-2 H,K-ATPase (HKA2) functioning under its Na+/K+ exchange mode. The first aim of this study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with sodium retention. The second aim of this study was to evaluate whether ANP-induced stimulation of sodium secretion by type-A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In Xenopus oocytes expressing HKA2, cGMP, the second messenger of ANP, increases the membrane expression, the activity and the Na+-transporting rate of HKA2. Feeding mice with a NH4Cl-enriched diet increased urinary excretion of aldosterone and induced a transient sodium retention that reversed within 3 days. At that time, expression of ANP mRNAs...

The Journal of Physiology, 2016

The cortical collecting duct (CCD) plays an essential role in sodium homeostasis by fine-tuning t... more The cortical collecting duct (CCD) plays an essential role in sodium homeostasis by fine-tuning the amount of sodium that is excreted in the urine. r Ex vivo, the microperfused CCD reabsorbs sodium in the absence of lumen-to-bath concentration gradients. r In the present study, we show that, in the presence of physiological lumen-to-bath concentration gradients, and in the absence of endocrine, paracrine and neural regulation, the mouse CCD secretes sodium, which represents a paradigm shift. r This secretion occurs via the paracellular route, as well as a transcellular pathway that is energized by apical H + /K +-ATPase type 2 pumps operating as Na + /K + exchangers. r The newly identified transcellular secretory pathway represents a physiological target for the regulation of sodium handling and for anti-hypertensive therapeutic agents.

World journal of biological chemistry, Jan 26, 2016

The renal handling of Na(+) balance is a major determinant of the blood pressure (BP) level. The ... more The renal handling of Na(+) balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na(+) represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na(+) excretion and are the target of many different regulatory processes that modulate Na(+) retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na(+) absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na(+) excretion, this review ...

The Journal of physiology, Jan 15, 2011

Nephrotic syndrome features massive proteinuria and retention of sodium which promotes ascite for... more Nephrotic syndrome features massive proteinuria and retention of sodium which promotes ascite formation. In the puromycin aminonucleoside-induced rat model of nephrotic syndrome, sodium retention originates from the collecting duct where it generates a driving force for potassium secretion. However, there is no evidence for urinary potassium loss or hypokalaemia in the nephrotic syndrome. We therefore investigated the mechanism preventing urinary potassium loss in the nephrotic rats and, for comparison, in hypovolaemic rats, another model displaying increased sodium reabsorption in collecting ducts. We found that sodium retention is not associated with urinary loss of potassium in either nephrotic or hypovolaemic rats, but that different mechanisms account for potassium conservation in the two models. Collecting ducts from hypovolaemic rats displayed high expression of the potassium-secreting channel ROMK but no driving force for potassium secretion owing to low luminal sodium avail...

Physiological Genomics, 2006

Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in a... more Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in acid or base dietary intake. Because collecting ducts constitute the final site for regulating urine acid-base balance, we undertook to identify the gene network involved in acid-base transport and regulation in the mouse outer medullary collecting duct (OMCD). For this purpose, we combined kidney functional studies and quantitative analysis of gene expression in OMCDs, by transcriptome and candidate gene approaches, during metabolic acidosis. Furthermore, to better delineate the set of genes concerned with acid-base disturbance, the OMCD transcriptome of acidotic mice was compared with that of both normal mice and mice undergoing an adaptative response through potassium depletion. Metabolic acidosis, achieved through an NH4Cl-supplemented diet for 3 days, not only induced acid secretion but also stimulated the aldosterone and vasopressin systems and triggered cell proliferation. Accordin...

Journal of Clinical Investigation, 2010

Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulat... more Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloridesensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na + and Clin mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na +-driven Cl-/HCO 3exchanger (NDCBE/SLC4A8) and the Na +-independent Cl-/HCO 3exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na + reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice. Authorship note: Françoise Leviel and Christian A. Hübner share first authorship.

Journal of Clinical Investigation, 2013

Values are means ± SD. Student's t-test. All urine and blood samples were collected from independ... more Values are means ± SD. Student's t-test. All urine and blood samples were collected from independent mice.

Journal of Biological Chemistry, 2013

Background: The function of proteinase-activated receptor 2 (PAR2) in the distal nephron remains ... more Background: The function of proteinase-activated receptor 2 (PAR2) in the distal nephron remains unknown. Results: PAR2 activation increases electroneutral sodium reabsorption and inhibits potassium secretion in collecting ducts and thereby controls blood pressure and plasma potassium. Conclusion: PAR2 controls sodium and potassium homeostasis. Significance: PAR2 is a new actor of aldosterone paradox but also an aldosterone-independent modulator of blood pressure and plasma potassium.

Journal of Biological Chemistry, 2008

Genes to Cells, 2003

Background : In Drosophila and vertebrates, suppressor of fused (Su(fu)) proteins act as negative... more Background : In Drosophila and vertebrates, suppressor of fused (Su(fu)) proteins act as negative regulators of the Gli / Ci transcription factors, which mediate the transcriptional effects of Hh signalling. Results : We sought for novel partners of Su(fu) in fly using the two-hybrid method. Most of the Su(fu) interactors thus identified are (or are likely to be) able to enter the nucleus. We focused on one of these putative partners, dMLF, which resembles vertebrate myelodysplasia/myeloid leukaemia factors 1 and 2. We demonstrate that dMLF binds specifically to Su(fu) in vitro and in vivo. Using a novel anti-dMLF antibody, we showed, that dMLF is a nuclear, chromosome-associated protein. We overexpressed a dMLF transgene in fly using an inducible expression system and showed that dMLF overexpression disrupts normal development, leading to either a lethal phenotype or adult structural defects associated with apoptosis and increased DNA synthesis. Furthermore, the dMLF-induced eye phenotype is enhanced by the loss of Su(fu) function, suggesting a genetic interaction between Su(fu) and dMLF. Conclusion : We propose that dSu(fu) and dMLF act together at the transcriptional level to coordinate patterning and proliferation during development.