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Piezo1-dependent regulation of urinary osmolarity

  • Ion channels, receptors and transporters
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Abstract

The collecting duct (CD) is the final segment of the kidney involved in the fine regulation of osmotic and ionic balance. During dehydration, arginine vasopressin (AVP) stimulates the expression and trafficking of aquaporin 2 (AQP2) to the apical membrane of CD principal cells, thereby allowing water reabsorption from the primary urine. Conversely, when the secretion of AVP is lowered, as for instance upon water ingestion or as a consequence of diabetes insipidus, the CD remains water impermeable leading to enhanced diuresis and urine dilution. In addition, an AVP-independent mechanism of urine dilution is also at play when fasting. Piezo1/2 are recently discovered essential components of the non-selective mechanically activated cationic channels. Using quantitative PCR analysis and taking advantage of a β-galactosidase reporter mouse, we demonstrate that Piezo1 is preferentially expressed in CD principal cells of the inner medulla at the adult stage, unlike Piezo2. Remarkably, siRNAs knock-down or conditional genetic deletion of Piezo1 specifically in renal cells fully suppresses activity of the stretch-activated non-selective cationic channels (SACs). Piezo1 in CD cells is dispensable for urine concentration upon dehydration. However, urinary dilution and decrease in urea concentration following rehydration are both significantly delayed in the absence of Piezo1. Moreover, decreases in urine osmolarity and urea concentration associated with fasting are fully impaired upon Piezo1 deletion in CD cells. Altogether, these findings indicate that Piezo1 is critically required for SAC activity in CD principal cells and is implicated in urinary osmoregulation.

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Acknowledgments

We are grateful to the ANR 2008 du gène à la physiopathologie; des maladies rares aux maladies communes, to the ANR 2011 physiologie, physiopathologie, santé publique, to the Fondation de la recherche médicale, to the Fondation de recherche sur l’hypertension artérielle, to the Fondation de France, to the Association Française contre les Myopathies (RP), to the Association pour l’information et la recherche sur les maladies rénales génétiques France, to the Région Provence Alpes Côte d’Azur, to the Société Française d’hypertension artérielle, to the Université de Nice Sophia Antipolis, and to the CNRS for financial support. JRM was a recipient of fellowship attributed by the Lefoulon-Delalande Fondation. We are grateful to Dr. Dorien Peters for sharing the KsprCre* mice with us and to Dr. Jacques Teulon for his help with the electrophysiology of isolated renal tubules.

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Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France

    Joana Raquel Martins, David Penton, Rémi Peyronnet, Malika Arhatte, Céline Moro, Amanda Patel, Eric Honoré & Sophie Demolombe

  2. Centre de Recherche des Cordeliers, CNRS ERL 8228, INSERM UMRS 1138, Université Pierre et Marie Curie, Paris, France

    Nicolas Picard

  3. Institute of Physiology, University of Regensburg, Regensburg, Germany

    Birgül Kurt

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  1. Joana Raquel Martins
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Correspondence to Eric Honoré.

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All experiments were performed according to policies on the care and use of laboratory animals of the European Community Legislation. The study was approved by the local committee for ethical and safety issues (CIEPAL-Azur).

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Eric Honoré is the co-last author.

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Fig. S1

Reversal potential of the SAC current in outer medulla tubule. Cell attached patch clamp recordings at the basal side of an isolated outer medulla collecting duct with a holding potential of -80 mV (top trace). Zero current is indicated by a dashed line and inward SAC currents are elicited in the control condition at increased negative pressure. Pressure pulses of increasing magnitude were applied at the back of the patch pipette using a fast pressure clamp system (bottom trace). At a holding potential of 0 mV (same patch), no SAC current was seen (middle trace). (DOCX 50 kb)

Fig. S2

Water intake and urine volume in control and Piezo1 knock-out mice before, during and after water deprivation. a Twenty-four-hour water intake before, during and after (1 and 24 hours) drinking deprivation in control (white bars) and knock-out (KspCre* Piezo1lox/lox, black bars) mice. b Urine volume. Data are presented as mean ± SEM. Number of mice is indicated in the bar graphs. (DOCX 64 kb)

Fig. S3

Food intake and body weight in control and Piezo1 knock-out mice before, during and after water deprivation. a Twenty-four-hour food intake before, during and 24 hours after drinking deprivation in control (white bars) and knock-out (KspCre* Piezo1lox/lox, black bars) mice. b Body weight. Data are presented as mean ± SEM. Number of mice is indicated in the bar graphs. (DOCX 54 kb)

Fig. S4

Water intake and urine volume in control and Piezo1 knock-out mice before and after fasting. a Twenty-four-hour water intake before and after food deprivation in control (white bars) and knock-out (KspCre* Piezo1lox/lox, black bars) mice. b Urine volume. Data are presented as mean ± SEM. Number of mice is indicated in the bar graphs. (DOCX 52 kb)

Fig. S5

Food intake and body weight in control and Piezo1 knock-out mice before and after fasting. a Twenty-four-hour food intake before food deprivation in control (white bars) and knock-out (KspCre* Piezo1lox/lox, black bars) mice. b Body weight before and after 24 h-food deprivation. Data are presented as mean ± SEM. Number of mice is indicated in the bar graphs. (DOCX 53 kb)

Fig. S6

Validation of the antibodies directed against total AQP2 and UT-A1 in the inner medulla (left) versus the cortex (right) of control kidneys. The predicted molecular weights of the non-glycosylated forms of AQP2 and UT-A1 are indicated by red arrows. The blot illustrated on top has first been probed with an antibody against GAPDH (visible as light white bands), then stripped and re-probed with the antibody against AQP2. No signal is detected, as expected, in the cortex with both AQP2 and UT-A1 antibodies. GAPDH expression was used as a loading control (bottom). (DOCX 138 kb)

Fig. S7

AQP2 and UT-A1 total protein expression in the inner medulla are independent of Piezo1 (WT: TAM-injected control mice, KO: TAM-injected KspCre* Piezo1del/lox mice). b AQP2 protein expression normalized to GAPDH in the inner medulla of TAM-injected control (white bars) and TAM-injected KspCre* Piezo1del/lox (black bars) mice. No significant difference is seen between both genotypes. Glycosylated, non-glycosylated and total AQP2 protein expression has been quantified. c UT-A1 protein expression (non-glycosylated) normalized to GAPDH in the inner medulla of TAM-injected control (white bars) and TAM-injected KspCre* Piezo1del/lox (black bars) mice. No significant difference is seen between both genotypes. GAPDH expression was used as a loading control (bottom). (DOCX 112 kb)

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Martins, J.R., Penton, D., Peyronnet, R. et al. Piezo1-dependent regulation of urinary osmolarity. Pflugers Arch - Eur J Physiol 468, 1197–1206 (2016). https://doi.org/10.1007/s00424-016-1811-z

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