Oppermann Mona, Mizel Diane, Kim Soo Mi, Chen Limeng, Faulhaber-Walter Robert, Huang Yuning, Li Cuiling, Deng Chuxia, Briggs Josie, Schnermann Jurgen, Castrop Hayo
NIDDK, NIH, Building 10, Room 4 D51, 10 Center Drive MSC-1370, Bethesda, MD 20892-1370, USA.
J Am Soc Nephrol. 2007 Feb;18(2):440-8. doi: 10.1681/ASN.2006091070. Epub 2007 Jan 10.
Three different full-length splice isoforms of the Na-K-2Cl co-transporter (NKCC2/BSC1) are expressed along the thick ascending limb of Henle (TAL), designated NKCC2A, NKCC2B, and NKCC2F. NKCC2F is expressed in the medullary, NKCC2B mainly in the cortical, and NKCC2A in medullary and cortical portions of the TAL. NKCC2B and NKCC2A were shown to be coexpressed in the macula densa (MD) segment of the mouse TAL. The functional consequences of the existence of three different isoforms of NKCC2 are unclear. For studying the specific role of NKCC2A in kidney function, NKCC2A-/- mice were generated by homologous recombination. NKCC2A-/- mice were viable and showed no gross abnormalities. Ambient urine osmolarity was reduced significantly in NKCC2A-/- compared with wild-type mice, but water deprivation elevated urine osmolarity to similar levels in both genotypes. Baseline plasma renin concentration and the effects of a high- and a low-salt diet on plasma renin concentration were similar in NKCC2A+/+ and -/- mice. However, suppression of renin secretion by acute intravenous saline loading (5% of body weight), a measure of MD-dependent inhibition of renin secretion, was reduced markedly in NKCC2A-/- mice compared with wild-type mice. Cl and water absorption along microperfused loops of Henle of NKCC2A-/- mice were unchanged at normal flow rates but significantly reduced at supranormal flow. Tubuloglomerular feedback function curve as determined by stop flow pressure measurements was left-shifted in NKCC2A-/- compared with wild-type mice, with maximum responses being significantly diminished. In summary, NKCC2A activity seems to be required for MD salt sensing in the high Cl concentration range. Coexpression of both high- and low-affinity isoforms of NKCC2 may permit transport and Cl-dependent tubuloglomerular feedback regulation to occur over a wider Cl concentration range.
钠-钾-2氯协同转运蛋白（NKCC2/BSC1）的三种不同全长剪接异构体在亨氏袢升支粗段（TAL）表达，分别命名为NKCC2A、NKCC2B和NKCC2F。NKCC2F在髓质表达，NKCC2B主要在皮质表达，NKCC2A在TAL的髓质和皮质部分均有表达。已证明NKCC2B和NKCC2A在小鼠TAL的致密斑（MD）段共表达。NKCC2三种不同异构体存在的功能后果尚不清楚。为了研究NKCC2A在肾功能中的特定作用，通过同源重组产生了NKCC2A基因敲除小鼠。NKCC2A基因敲除小鼠存活且无明显异常。与野生型小鼠相比，NKCC2A基因敲除小鼠的尿渗透压显著降低，但禁水后两种基因型的尿渗透压均升高至相似水平。NKCC2A+/+和-/-小鼠的基础血浆肾素浓度以及高盐和低盐饮食对血浆肾素浓度的影响相似。然而，与野生型小鼠相比，NKCC2A基因敲除小鼠经急性静脉注射生理盐水（体重的5%）负荷后肾素分泌的抑制作用明显减弱，这是一种衡量MD依赖性肾素分泌抑制的指标。在正常流速下，NKCC2A基因敲除小鼠的亨氏袢微灌注段对氯和水的重吸收未发生变化，但在超常流速下显著降低。与野生型小鼠相比，通过停流压力测量确定的肾小管-肾小球反馈功能曲线在NKCC2A基因敲除小鼠中向左移位，最大反应显著减弱。总之，在高氯浓度范围内，MD盐感应似乎需要NKCC2A的活性。NKCC2高亲和力和低亲和力异构体的共表达可能使转运以及氯依赖性肾小管-肾小球反馈调节在更宽的氯浓度范围内发生。
