Are Sodium Transporters in Urinary Exosomes Reliable Markers of Tubular Sodium Reabsorption in Hypertensive Patients?

Overview

Journal Nephron Physiol

Publisher Karger

Specialties Cell Biology
Nephrology

Date 2010 Jan 14

PMID 20068364

Citations 21

Authors

Cristina Esteva-Font

Xiaoyan Wang

Elisabet Ars

Elena Guillen-Gomez

Laia Sans

Isabel Gonzalez Saavedra

Ferran Torres

Roser Torra

Shyama Masilamani

Jose Aurelio Ballarin

Patricia Fernandez-Llama

Affiliations

Soon will be listed here.

Abstract

Background: Altered renal sodium handling has a major pathogenic role in salt-sensitive hypertension. Renal sodium transporters are present in urinary exosomes. We hypothesized that sodium transporters would be excreted into the urine in different amounts in response to sodium intake in salt-sensitive versus salt-resistant patients.

Methods: Urinary exosomes were isolated by ultracentrifugation, and their content of Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC) was analyzed by immunoblotting. Animal studies: NKCC2 and NCC excretion was measured in 2 rat models to test whether changes in sodium transporter excretion are indicative of regulated changes in the kidney tissue. Human studies: in hypertensive patients (n = 41), we investigated: (1) a possible correlation between sodium reabsorption and urinary exosomal excretion of sodium transporters, and (2) the profile of sodium transporter excretion related to blood pressure (BP) changes with salt intake. A 24-hour ambulatory BP monitoring and a 24-hour urine collection were performed after 1 week on a low- and 1 week on a high-salt diet.

Results: Animal studies: urinary NKCC2 and NCC excretion rates correlated well with their abundance in the kidney. Human studies: 6 patients (15%) were classified as salt sensitive. The NKCC2 and NCC abundance did not decrease after the high-salt period, when the urinary sodium reabsorption decreased from 99.7 to 99.0%. In addition, the changes in BP with salt intake were not associated with a specific profile of exosomal excretion.

Conclusions: Our results do not support the idea that excretion levels of NKCC2 and NCC via urinary exosomes are markers of tubular sodium reabsorption in hypertensive patients.

Citing Articles

Sodium Chloride Cotransporter in Hypertension.

Castagna A, Mango G, Martinelli N, Marzano L, Moruzzi S, Friso S Biomedicines. 2024; 12(11).

PMID: 39595146 PMC: 11591633. DOI: 10.3390/biomedicines12112580.

Effect of the DASH diet on the sodium-chloride cotransporter and aquaporin-2 in urinary extracellular vesicles.

Bielopolski D, Musante L, Hoorn E, Molina H, Barrows D, Carrol T Am J Physiol Renal Physiol. 2024; 326(6):F971-F980.

PMID: 38634133 PMC: 11386975. DOI: 10.1152/ajprenal.00274.2023.

β3 Adrenergic Receptor Agonist Mirabegron Increases AQP2 and NKCC2 Urinary Excretion in OAB Patients: A Pleiotropic Effect of Interest for Patients with X-Linked Nephrogenic Diabetes Insipidus.

Milano S, Maqoud F, Rutigliano M, Saponara I, Carmosino M, Gerbino A Int J Mol Sci. 2023; 24(2).

PMID: 36674662 PMC: 9865646. DOI: 10.3390/ijms24021136.

uEVs: A Potential Tool for Examining Renal Epithelial Cells.

Deck K, Mu S Kidney360. 2022; 3(5):796-798.

PMID: 36128488 PMC: 9438409. DOI: 10.34067/KID.0001832022.

Using human urinary extracellular vesicles to study physiological and pathophysiological states and regulation of the sodium chloride cotransporter.

Wu A, Wolley M, Fenton R, Stowasser M Front Endocrinol (Lausanne). 2022; 13:981317.

PMID: 36105401 PMC: 9465297. DOI: 10.3389/fendo.2022.981317.

References

Weinberger M . Salt sensitivity of blood pressure in humans. Hypertension. 1996; 27(3 Pt 2):481-90. DOI: 10.1161/01.hyp.27.3.481. View

Alvarez-Guerra M, Garay R . Renal Na-K-Cl cotransporter NKCC2 in Dahl salt-sensitive rats. J Hypertens. 2002; 20(4):721-7. DOI: 10.1097/00004872-200204000-00031. View

Pieper R, Gatlin C, McGrath A, Makusky A, Mondal M, Seonarain M . Characterization of the human urinary proteome: a method for high-resolution display of urinary proteins on two-dimensional electrophoresis gels with a yield of nearly 1400 distinct protein spots. Proteomics. 2004; 4(4):1159-74. DOI: 10.1002/pmic.200300661. View

Zhou H, Yuen P, Pisitkun T, Gonzales P, Yasuda H, Dear J . Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int. 2006; 69(8):1471-6. PMC: 2276656. DOI: 10.1038/sj.ki.5000273. View

Lifton R, Gharavi A, Geller D . Molecular mechanisms of human hypertension. Cell. 2001; 104(4):545-56. DOI: 10.1016/s0092-8674(01)00241-0. View

Hoagland K, Flasch A, Dahly-Vernon A, dos Santos E, Knepper M, Roman R . Elevated BSC-1 and ROMK expression in Dahl salt-sensitive rat kidneys. Hypertension. 2004; 43(4):860-5. DOI: 10.1161/01.HYP.0000120123.44945.47. View

GUYTON A . Blood pressure control--special role of the kidneys and body fluids. Science. 1991; 252(5014):1813-6. DOI: 10.1126/science.2063193. View

Pickering T . The clinical significance of diurnal blood pressure variations. Dippers and nondippers. Circulation. 1990; 81(2):700-2. DOI: 10.1161/01.cir.81.2.700. View

Sachdeva A, Weder A . Nocturnal sodium excretion, blood pressure dipping, and sodium sensitivity. Hypertension. 2006; 48(4):527-33. DOI: 10.1161/01.HYP.0000240268.37379.7c. View

10.

Chiolero A, Maillard M, Nussberger J, Brunner H, Burnier M . Proximal sodium reabsorption: An independent determinant of blood pressure response to salt. Hypertension. 2000; 36(4):631-7. DOI: 10.1161/01.hyp.36.4.631. View

11.

McKee J, Kumar S, Ecelbarger C, Fernandez-Llama P, Terris J, Knepper M . Detection of Na(+) transporter proteins in urine. J Am Soc Nephrol. 2000; 11(11):2128-2132. DOI: 10.1681/ASN.V11112128. View

12.

Fernandez-Llama P, Ageloff S, Fernandez-Varo G, Ros J, Wang X, Garra N . Sodium retention in cirrhotic rats is associated with increased renal abundance of sodium transporter proteins. Kidney Int. 2005; 67(2):622-30. DOI: 10.1111/j.1523-1755.2005.67118.x. View

13.

Masilamani S, Wang X, Kim G, Brooks H, Nielsen J, Nielsen S . Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction. Am J Physiol Renal Physiol. 2002; 283(4):F648-57. DOI: 10.1152/ajprenal.00016.2002. View

14.

Rossier B . 1996 Homer Smith Award Lecture. Cum grano salis: the epithelial sodium channel and the control of blood pressure. J Am Soc Nephrol. 1997; 8(6):980-92. DOI: 10.1681/ASN.V86980. View

15.

Pedersen R, Bentzen H, Bech J, Nyvad O, Pedersen E . Urinary aquaporin-2 in healthy humans and patients with liver cirrhosis and chronic heart failure during baseline conditions and after acute water load. Kidney Int. 2003; 63(4):1417-25. DOI: 10.1046/j.1523-1755.2003.00858.x. View

16.

Wang X, Masilamani S, Nielsen J, Kwon T, Brooks H, Nielsen S . The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon. J Clin Invest. 2001; 108(2):215-22. PMC: 203017. DOI: 10.1172/JCI10366. View

17.

Masilamani S, Kim G, Mitchell C, Wade J, Knepper M . Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Invest. 1999; 104(7):R19-23. PMC: 408561. DOI: 10.1172/JCI7840. View

18.

Gonzales P, Pisitkun T, Hoffert J, Tchapyjnikov D, Star R, Kleta R . Large-scale proteomics and phosphoproteomics of urinary exosomes. J Am Soc Nephrol. 2008; 20(2):363-79. PMC: 2637050. DOI: 10.1681/ASN.2008040406. View

19.

Wen H, Frokiaer J, Kwon T, Nielsen S . Urinary excretion of aquaporin-2 in rat is mediated by a vasopressin-dependent apical pathway. J Am Soc Nephrol. 1999; 10(7):1416-29. DOI: 10.1681/ASN.V1071416. View

20.

Kim G, Masilamani S, Turner R, Mitchell C, Wade J, Knepper M . The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci U S A. 1998; 95(24):14552-7. PMC: 24411. DOI: 10.1073/pnas.95.24.14552. View