Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Department of Veterinary Medicine and Animal Productions, University of Naples, Naples, Italy.
Nephrol Dial Transplant. 2024 Jan 31;39(2):297-304. doi: 10.1093/ndt/gfad161.
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 having CsA treatment were enrolled in the study.
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 were challenged with 50 mg furosemide.
CsA-treated rats developed hypertension associated with reduced glomerular filtration rate. In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption in the proximal tubule but enhanced sodium reabsorption in the 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 the inner stripe of outer medulla. 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 with both healthy controls and FK506-treated transplanted patients.
Altogether, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension.
环孢素 A（CsA）的应用受到肾毒性的限制，包括高血压，这部分依赖于肾钠潴留。为了解决这个问题，我们通过微穿刺研究结合钠转运体的表达分析，研究了 CsA 治疗大鼠不同肾单位段的体内钠重吸收。为了将大鼠的研究结果转化为人类，我们招募了接受 CsA 治疗的肾移植患者进行研究。
成年雄性 Sprague-Dawley 大鼠接受 CsA（15mg/kg/天）治疗 21 天，然后进行微穿刺研究和钠转运体表达分析。CsA 治疗的肾移植高血压耐药患者接受 50mg 呋塞米挑战。
CsA 治疗的大鼠出现高血压，伴肾小球滤过率降低。体内微灌注研究表明，近端小管绝对液体重吸收率显著降低，但 Henle 袢升支厚段（TAL）的钠重吸收增强。同一肾单位段的钠转运体表达分析进一步显示，皮质 NHE3 减少，而 TAL 特异性、呋塞米敏感的 Na+-K+-2Cl-共转运体（NKCC2）和 NHE3 在外髓内层明显上调。CsA 治疗的患者在基础状态下尿 NKCC2 蛋白排泄量更大，对呋塞米的利尿反应更高，与健康对照组和 FK506 治疗的移植患者相比，FeNa+、FeCl-和 FeCa2+均升高。
综上所述，这些发现表明 NKCC2 在 TAL 中的上调促进了钠的重吸收，导致 CsA 诱导的高血压的发生。
