Background: The use of Cyclosporin A (CsA) is hampered by the development of nephrotoxicity including hypertension, which is partially dependent on renal sodium retention. To address this issue, we have investigated in vivo sodium reabsorption in different nephron segments of CsA-treated rats through micropuncture study coupled to expression analyses of sodium transporters. To translate the findings in rats to human, kidney transplanted patients with CsA treatment were enrolled in the study. Methods: Adult male Sprague-Dawley rats were treated with CsA (15 mg/kg/day) for 21 days, followed by micropuncture study and expression analyses of sodium transporters. CsA-treated kidney transplanted patients with resistant hypertension have been challenged with 50 mg furosemide. Results: CsA-treated rats developed hypertension associated with reduced glomerular filtration rate (GFR). In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption (Jv) in the proximal tubule (PT) but enhanced sodium reabsorption (JNa) in thick ascending limb of Henle's loop (TAL). Expression analyses of sodium transporters at the same nephron segments further revealed a reduction in Na+-H+ exchanger isoform 3 (NHE3) in the renal cortex, while TAL-specific, furosemide-sensitive Na+-K+-2Cl- cotransporter (NKCC2) and NHE3 were significantly upregulated in ISOM. CsA-treated patients had a larger excretion of urinary NKCC2 protein at basal condition, and higher diuretic response to furosemide, showing increased FeNa+, FeCl- and FeCa2+ compared to both healthy controls and FK506-treated transplanted patients. Conclusion: All together, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension.

Cyclosporin-induced hypertension is associated with the up-regulation of Na+-K+-2Cl- cotransporter (NKCC2) / Capolongo, Giovanna; Damiano, Sara; Suzumoto, Yoko; Zacchia, Miriam; Rizzo, Maria; Zona, Enrica; Pollastro, Rosa Maria; Simeoni, Mariadelina; Ciarcia, Roberto; Trepiccione, Francesco; Capasso, Giovambattista. - In: NEPHROLOGY DIALYSIS TRANSPLANTATION. - ISSN 0931-0509. - 0:(2023), pp. 1-8. [10.1093/ndt/gfad161]

Cyclosporin-induced hypertension is associated with the up-regulation of Na+-K+-2Cl- cotransporter (NKCC2)

Damiano, Sara
Secondo
;
Ciarcia, Roberto;Trepiccione, Francesco;
2023

Abstract

Background: The use of Cyclosporin A (CsA) is hampered by the development of nephrotoxicity including hypertension, which is partially dependent on renal sodium retention. To address this issue, we have investigated in vivo sodium reabsorption in different nephron segments of CsA-treated rats through micropuncture study coupled to expression analyses of sodium transporters. To translate the findings in rats to human, kidney transplanted patients with CsA treatment were enrolled in the study. Methods: Adult male Sprague-Dawley rats were treated with CsA (15 mg/kg/day) for 21 days, followed by micropuncture study and expression analyses of sodium transporters. CsA-treated kidney transplanted patients with resistant hypertension have been challenged with 50 mg furosemide. Results: CsA-treated rats developed hypertension associated with reduced glomerular filtration rate (GFR). In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption (Jv) in the proximal tubule (PT) but enhanced sodium reabsorption (JNa) in thick ascending limb of Henle's loop (TAL). Expression analyses of sodium transporters at the same nephron segments further revealed a reduction in Na+-H+ exchanger isoform 3 (NHE3) in the renal cortex, while TAL-specific, furosemide-sensitive Na+-K+-2Cl- cotransporter (NKCC2) and NHE3 were significantly upregulated in ISOM. CsA-treated patients had a larger excretion of urinary NKCC2 protein at basal condition, and higher diuretic response to furosemide, showing increased FeNa+, FeCl- and FeCa2+ compared to both healthy controls and FK506-treated transplanted patients. Conclusion: All together, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension.
2023
Cyclosporin-induced hypertension is associated with the up-regulation of Na+-K+-2Cl- cotransporter (NKCC2) / Capolongo, Giovanna; Damiano, Sara; Suzumoto, Yoko; Zacchia, Miriam; Rizzo, Maria; Zona, Enrica; Pollastro, Rosa Maria; Simeoni, Mariadelina; Ciarcia, Roberto; Trepiccione, Francesco; Capasso, Giovambattista. - In: NEPHROLOGY DIALYSIS TRANSPLANTATION. - ISSN 0931-0509. - 0:(2023), pp. 1-8. [10.1093/ndt/gfad161]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/942661
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