Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2)

Esteva‐Font, Cristina; Ars, Elisabet; Guillén‐Gómez, Elena; Campistol, Josep M.; Sanz, Laia; Jiménez, Wladimiro; Knepper, Mark A.; Torres, Ferrán; Torra, Roser; Ballarín, José; Fernández-Llama, Patricia

doi:10.1093/ndt/gfm390

Cited by 43 publications

(28 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The abundance of Na-K-ATPase α 1 -subunit protein was not significantly changed, and NKCC2 was unchanged in cortex but remarkably increased in medulla (data not shown). The latter finding is consistent with the recent report by Esteva-Font et al [23]. …”

Section: Discussionsupporting

confidence: 94%

See 1 more Smart Citation

Altered Expression of Tight Junction Proteins in Cyclosporine Nephrotoxicity

Lee

Kim²,

Kang³

et al. 2010

Am J Nephrol

View full text Add to dashboard Cite

Background/Aims: The increased permeability of chloride in the distal cortical nephron in cyclosporine nephrotoxicity may involve the transcellular pathway mediated by the thiazide-sensitive Na⁺-Cl^– cotransporter and/or the paracellular pathway mediated by the tight junctions (TJs). Methods: Cyclosporine was subcutaneously administered to Sprague-Dawley rats for 6 (7.5 mg/kg body weight) and 2 (25 mg/kg body weight) weeks, and immunoblot analysis and immunohistochemistry were carried out from the kidneys. Electrically tight epithelial Madin-Darby canine kidney (MDCK) I cells were exposed to cyclosporine for 72 h to measure changes in transepithelial electrical resistance (ΔTER). Results: Cyclosporine treatment induced a decrease in Na⁺-Cl^– cotransporter in rat renal cortex. WNK4 protein was increased in both rat kidneys and MDCK I cells. Occludin was also increased in rat kidneys and MDCK I cells exposed to 100 ng/ml cyclosporine. In contrast, cyclosporine treatment induced a decrease in zonula occludens 1 protein abundance and no changes in claudin-1 and claudin-4 in both rat kidneys and MDCK I cells. As a measure of the barrier to small ions, ΔTER of MDCK monolayers was decreased by 100 ng/ml cyclosporine. Conclusion: Renal TJ proteins are affected by cyclosporine treatment. Changes in TJ protein assembly induced by altered expression of WNK4, occludin, and zonula occludens 1 may affect paracellular permeability.

show abstract

Section: Discussionsupporting

confidence: 94%

“…Alteration of renal sodium transporters was previously reported in cyclosporine-treated rats [22,23]. Lim et al [22] used cyclosporine (15 mg/kg BW) subcutaneously for 28 days in rats fed low-salt diet, and found nonselective downregulation of NKCC2, NCC and Na-K-ATPase.…”

Section: Discussionmentioning

confidence: 89%

Altered Expression of Tight Junction Proteins in Cyclosporine Nephrotoxicity

Lee

Kim²,

Kang³

et al. 2010

Am J Nephrol

View full text Add to dashboard Cite

show abstract

“…An experimental model of hypertension induced by CsA showed an increase in NKCC2 in rat kidneys [10]. Tacrolimus is involved in renal NCC activation associated with hypertension [11].…”

Section: Discussionmentioning

confidence: 99%

“…In cultured cells, CsA induced an increase in bumetanide-sensitive sodium potassium-2 chloride cotransporter (NKCC2) activity [9]. On the other hand, a previous study from our laboratory showed that in rats with CsA-induced hypertension, NKCC2 protein and mRNA expression levels were markedly increased in the kidneys [10]. Hoorn et al [11] reported that tacrolimus-induced hypertension was mediated by sodium chloride cotransporter (NCC) activation in rats.…”

Section: Introductionmentioning

confidence: 99%

Renal Sodium Transporters Are Increased in Urinary Exosomes of Cyclosporine-Treated Kidney Transplant Patients

et al. 2014

View full text Add to dashboard Cite

Background/Aims: Cyclosporine (CsA) is a calcineurin inhibitor widely used as an immunosuppressant in organ transplantation. Previous studies demonstrated the relationship between CsA and renal sodium transporters such as the Na-K-2Cl cotransporter in the loop of Henle (NKCC2). Experimental models of CsA-induced hypertension have shown an increase in renal NKCC2. Methods: Using immunoblotting of urinary exosomes, we investigated in CsA-treated kidney transplant patients (n = 39) the excretion of NKCC2 and Na-Cl cotransporter (NCC) and its association with blood pressure (BP) level. We included 8 non-CsA-treated kidney transplant patients as a control group. Clinical data, immunosuppression and hypertension treatments, blood and 24-hour urine tests, and 24-hour ambulatory BP monitoring were recorded. Results: CsA-treated patients tended to excrete a higher amount of NKCC2 than non-CsA-treated patients (mean ± SD, 175 ± 98 DU and 90 ± 70.3 DU, respectively; p = 0.05) and showed higher BP values (24-hour systolic BP 138 ± 17 mm Hg and 112 ± 12 mm Hg, p = 0.003; 24-hour diastolic BP, 83.8 ± 9.8 mm Hg and 72.4 ± 5.2 mm Hg, p = 0.015, respectively). Within the CsA-treated group, there was no correlation between either NKCC2 or NCC excretion and BP levels. This was confirmed by a further analysis including potential confounding factors. On the other hand, a significant positive correlation was observed between CsA blood levels and the excretion of NKCC2 and NCC. Conclusion: Overall, these results support the hypothesis that CsA induces an increase in NKCC2 and NCC in urinary exosomes of renal transplant patients. The fact that the increase in sodium transporters in urine did not correlate with the BP level suggests that in kidney transplant patients, other mechanisms could be implicated in CsA-induced hypertension.

show abstract

“…Esteva-Font et al [33] demonstrated an increase in the Na-K-2Cl (NKCC2) cotransporter in the loop of Henle in rats treated with CsA (25 mg/kg/day IP for 7 days). Lee et al [34] demonstrated a decrease in Na-Cl cotransporter in renal cortex of rats treated with CsA and also demonstrated that occludin was also increased in rat kidneys exposed to CsA.…”

Section: Csa and Srl: In Vivo Experimental Studiesmentioning

confidence: 99%

Enhancement of Renal Tubular Epithelial Cell Barrier Function by the Immunosuppressant Drugs Cyclosporine A and Sirolimus

Slattery¹

2012

JEBP

View full text Add to dashboard Cite

Abstract:The primary function of the kidney includes the elimination of waste products and the maintenance of fluid and electrolyte composition of the body. The functioning unit of the kidney is the nephron including the glomerulus with a filtration function and the tubule with a reabsorption and secretion function. The fluid and electrolyte homeostasis is achieved largely through selective, vectorial transport facilitated by the renal tubular epithelium. This involves both transcellular and paracellular transport. Paracellular transport across renal tubular epithelial tight junctions (TJs) varies in different parts of the nephron. The relative concentrations of different claudins that are located in the TJ at any time determine the ion and size selectivity of the paracellular diffusion pathway in the kidney as in other tissues. In this article, we review work from our own laboratory and others providing evidence that immunosuppressive drugs, especially cyclosporine A (CsA) and sirolimus (SRL) and can alter transport molecules in kidney tubules. We outline evidence that CsA and SRL can enhance renal epithelial barrier function as indicated by transepithelial electrical resistance (TEER). The possible signalling mechanisms involved in altering the TJs and claudins by CsA and SRL are outlined and involve both TGF-1 and the ERK 1/2. These effects of CsA and SRL on kidney epithelia cell barrier function may help to explain some of the renal transport defects and nephrotoxicity seen with CsA and SRL. However if similar effects occur systemically in vivo, with these two immunosuppressive drugs, the enhancement of barrier function in areas of the body may decrease luminal antigen presentation, decreasing immune activation and support the immunosuppressive action of these drugs.Keywords: Tubular epithelial cells, rapamycin, sirolimus, cyclosporine. BARRIER FUNCTION OF THE RENAL TUBULAR EPITHELIUMThe primary function of the kidney includes the elimination of waste products and the maintenance of fluid and electrolyte composition of the body. The functioning unit of the kidney is the nephron including the glomerulus with a filtration function and the tubule with a reabsorption and secretion function. The fluid and electrolyte homeostasis is achieved largely through selective, vectorial transport facilitated by the renal tubular epithelium. The reabsorption and secretion of various solutes across the renal tubular epithelium constitutes a major aspect of kidney function. The primary characteristic of all epithelial cells, including kidney epithelial cells, is the ability to act as selective barriers between compartments in the body. This is accomplished by the fact that epithelial cells are polarized (i.e. they have distinct apical and basolateral domains). Therefore, epithelial layers can act as asymmetric transporters of salts, nonelectrolytes and water thereby regulating the volume and composition of the compartments on either side. Epithelial cells adhere to each other through molecular complexes that form junctions be...

show abstract

Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2)

Abstract: Our results pointed to the thick ascending limb of the loop of Henle as an important site of sodium retention in cyclosporine-induced hypertension. This data may have potential clinical implications for the treatment of hypertension induced by cyclosporine.

Cited by 43 publications

References 20 publications

Altered Expression of Tight Junction Proteins in Cyclosporine Nephrotoxicity

Altered Expression of Tight Junction Proteins in Cyclosporine Nephrotoxicity

Renal Sodium Transporters Are Increased in Urinary Exosomes of Cyclosporine-Treated Kidney Transplant Patients

Enhancement of Renal Tubular Epithelial Cell Barrier Function by the Immunosuppressant Drugs Cyclosporine A and Sirolimus

Contact Info

Product

Resources

About