Stockand J D, Sansom S C
Department of Internal Medicine, University of Texas Medical School at Houston 77030, USA.
Am J Kidney Dis. 1997 Jun;29(6):971-81. doi: 10.1016/s0272-6386(97)90476-5.
The rate of renal filtration is in large part responsible for volume and electrolyte balance in an organism. Integral components of the renal glomerulus are the mesangial cells (MCs), excitable renal pericytes that regulate the glomerular filtration rate by modulating the surface area of the capillaries. Similar to vascular smooth muscle, the signal transduction pathways and ion selective channels regulating isotonic and isometric contraction of MCs are dependent on the voltage-gated Ca influx. During the response to contractile agonists, both Cl and nonselective cation channels play critical roles to depolarize the membrane potential and activate Ca channels. The relaxation pathways involve a negative-feedback mechanism that counteracts mesangial contraction by regulating voltage-dependent Ca signaling. Part of the feedback response involves the activation of plasmalemmal K channels, which hyperpolarize the membrane potential and inhibit voltage-gated Ca entry. This calcium- and voltage-activated feedback K (BKCa) channel shares biophysical, pharmacologic, and molecular properties with the BKCa channels identified in brain and muscle, and with the sio gene product as expressed in Xenopus laevis oocytes. Systemic hormones, such as atrial natriuretic peptide, and paracrine factors, such as nitric oxide (NO), use guanosine 3',5'-cyclic monophosphate (GMP) as a second messenger and enhance the gain in this feedback system by decreasing the voltage and Ca activation thresholds for BKCa. Diabetes mellitus is often associated with high rates of glomerular filtration, mesangial expansion, and secretory abnormalities of the basement membrane. NO-mediated increases in negative-feedback regulation of mesangial tone may attribute, in part, to the pathology of hyperfiltration. Stimulation of inducible nitric oxide synthetase in glomerular MCs by inflammatory cytokines is a possible positive-feedback pathway that contributes to further glomerular destruction. In addition, high ambient glucose, through modulation of BKCa activity, facilitates MC relaxation and thus propagates hyperfiltration. Since cellular arachidonic acid is metabolically linked to extracellular glucose, this fatty acid is a possible mediator of the pathologic actions of hyperglycemia. Clarification of the signal transduction pathways and ionic mechanisms regulating the normal and dysfunctional tones of MCs is essential for rational clinical management of glomerular disease and critical to understanding fluid and electrolyte homeostasis.
肾滤过率在很大程度上负责生物体的容量和电解质平衡。肾小球的重要组成部分是系膜细胞（MCs），它们是可兴奋的肾周细胞，通过调节毛细血管表面积来调节肾小球滤过率。与血管平滑肌类似，调节MCs等渗和等长收缩的信号转导途径和离子选择性通道依赖于电压门控钙内流。在对收缩性激动剂的反应过程中，氯离子通道和非选择性阳离子通道都在使膜电位去极化和激活钙通道方面发挥关键作用。舒张途径涉及一种负反馈机制，该机制通过调节电压依赖性钙信号来抵消系膜收缩。部分反馈反应涉及质膜钾通道的激活，该通道使膜电位超极化并抑制电压门控钙内流。这种钙和电压激活的反馈性钾通道（BKCa）与在脑和肌肉中鉴定出的BKCa通道以及在非洲爪蟾卵母细胞中表达的sio基因产物具有生物物理、药理和分子特性。全身激素，如心房利钠肽，以及旁分泌因子，如一氧化氮（NO），使用鸟苷3',5'-环磷酸（GMP）作为第二信使，并通过降低BKCa的电压和钙激活阈值来增强该反馈系统的增益。糖尿病常与高肾小球滤过率、系膜扩张和基底膜分泌异常相关。NO介导的系膜张力负反馈调节增加可能部分归因于超滤过的病理状态。炎症细胞因子刺激肾小球MCs中的诱导型一氧化氮合酶是一种可能的正反馈途径，有助于进一步的肾小球破坏。此外，高环境葡萄糖通过调节BKCa活性促进MC舒张，从而加剧超滤过。由于细胞花生四烯酸在代谢上与细胞外葡萄糖相关联，这种脂肪酸可能是高血糖病理作用的介质。阐明调节MCs正常和功能失调张力的信号转导途径和离子机制对于肾小球疾病的合理临床管理至关重要，并且对于理解体液和电解质稳态至关重要。
