幻灯片 1

Transcription

1 ORGANIZATION OF THE URINARY SYSTEM

2 泌尿系统 输尿管 肾上腺 肾脏 膀胱

3 1/ 肾门 hilus 是神经 动脉进入, 静脉 淋巴管 输尿管离开 2/ 入肾门是肾窦 renal sinus, 与输尿管 ureter 相连 肾窦充满尿液 : 包括肾盂 renal pelvis 及其肾大 肾小盏 major minor 静 calyces 脉 3/ 血管和神经通过肾窦进入肾脏 4/ 肾囊或肾被膜 renal capsule 从肾门进入肾窦, 被膜内层形成肾窦衬里, 外层固定血管和肾盂 renal pelvis 肾盂 纤维被膜 肾窦 肾门 hilus 肾动脉 髓质线 输尿管 皮质 肾髓质分为 8-18 个肾锥 pyramid, 其基底部在皮 髓交界处, 顶部向肾盂 肾锥尖有微开孔, 肉眼几不可见, 所生成尿液通过此处流入肾窦的肾小盏肾脏分为皮质 ( 颗粒状外层 ) 和髓质 ( 暗内层 ) 皮层颗粒状是因肾小球的存在, 即超微毛细血管丛, 及曲小管的存在 髓质无肾小球, 但有垂直的平行肾小管和直小血管 肾锥乳突 髓质 ( 肾锥 ) 被膜 肾大盏 肾小盏 叶间动脉

4 高血流量的肾及肾小球毛细血管入 出球小动脉 小叶间静脉 出球小动脉入球小动脉 近髓肾小球 3/ 弓状动脉分支 ( 小叶间动脉近端 ) 灌注皮髓边界近髓 juxtamedullary 肾小球 这些肾小球出球小动脉进入肾乳突 papillae 形成发卡样直血管 vasa recta, 即髓质肾小球毛细血管网 肾血 90% 灌注肾皮质及表层肾小球 ;10% 灌注髓质和近髓肾小球 4/ 淋巴管引流皮层间质液, 含高浓度肾激素如红细胞生成素 erythropoietin, 淋巴管延肾动脉走向肾门 肾髓质无淋巴管, 不然浓缩尿所必须髓质高渗间质液也会被引流 星状静脉 弓状动静脉升降支直血管 肾髓质 ( 肾锥 ) 贝氏管 亨氏袢 叶间静脉 叶间动脉 肾被膜 肾皮质 表浅肾小球小叶间静脉管周血管床 1/ 肾脏重只占体重 < 0.5%, 血流量可占心输出量 20% 有足够血浆供肾小球形成超滤液 ultrafiltrate 肾循环血管顺序是 : 高阻力入球小动脉 高阻力肾小球毛细血管 高阻力出球小动脉 - 肾小管旁 (peritubular) 低压毛细血管网 低压毛细血管吸收肾小管所摄取液体 2/ 肾动脉入肾门后分前后分支, 进一步分支为叶间 interlobar 弓状 arcuate 动脉 弓状动脉位于皮髓 corticomedullary 边界并在此处分支为上升小叶间动脉 ascending interlobular arteries 进入皮质, 发出传入 afferent 小动脉 传入小动脉之后是肾小球毛细血管, 及传出 efferent 小动脉 对于浅皮质肾单元来说, 出球小动脉继续前行, 形成肾小管周 peritubular 致密毛细血管床, 为皮质肾小管提供氧气和营养 传入和出球小动脉决定了肾小球毛细血管的液体静 hydrostatic 压 小动脉张力受到丰富交感神经末梢支配, 也受到体液化学信号的调控

5 肾脏的功能单元式肾单元 The functional unit of the kidney is the nephron 肾脏含 800,000-1,200,000 个肾单元 每个肾单元是独立功能单位, 在初始收集管与其它单元集合至收集管 肾单元含肾小球 glomerulus 和肾小管 tubule 两部分 肾小球是一簇血管, 过滤血浆 肾小管上皮组成不同分段结构, 将血浆过滤液转换为尿液 肾小球和肾小管 分别对应血管和上皮 在肾小管上皮盲端汇合, 是为勃氏 Bowman s 囊或肾小球囊 肾小球囊包裹肾小球, 囊中是勃氏腔 勃氏腔与肾小管相通, 在此处血浆过滤液从血管系统进入肾小管上皮 肾单元其余部分是分段肾小管 肾单元上皮部包括勃氏囊, 近端 proximal 曲 直小管, 下降 上升支细亨氏袢 loop of Henle, 上升支粗亨氏袢, 远端曲 convoluted 小管, 和连接 connecting 管 连接管汇入初始收集管 initial collecting tubule, 皮质和髓质收集管 肾皮层含两类肾单元 : 表浅 superficial 和近球 juxtamedullary 肾单元 浅表肾单元韩氏袢较短, 下降至内外髓质分界处 近球肾单元韩式袢长, 可下降至肾髓顶尖, 在尿浓缩过程发挥重要作用 连接管 勃氏囊 近端曲小管近端直小管降细亨氏袢 Figure 33-2 Structure of the nephron 初始收集管连接管远端曲小管 皮质收集管外髓收集管升细亨氏袢 近端曲小管近端直小管升粗致亨氏 袢 内髓收集管 贝氏管 密 斑

6 肾小体 ( 肾小球和勃氏囊 ) 的发生 The renal corpuscle, the site of formation of the glomerular filtrate, comprises a glomerulus, Bowman s space, and Bowman s capsule. 松散间充质聚集 S 形中空管远端 松散间充质上皮输尿管芽 入球小动脉 壁层脏层 小管加长 出球小动脉 远端足细胞 勃氏囊近端 足细胞 近端足细胞折叠

7 肾小体 ( 肾小球和勃氏囊 ) 的结构 I 勃氏囊壁层勃氏囊腔 近端曲小管 尿液极 勃氏囊 勃氏囊脏层 ( 足细胞 ) 入球小动脉 基底膜血管极 出球小动脉近球器基底层 系膜细胞及球外间质 升支粗管远端小管 远端小管致密斑 近球颗粒细胞 成熟肾脏足细胞的足突起覆盖肾小球毛细血管 足细胞是特华得上皮细胞, 属于勃氏囊脏层细胞 在肾小体血管极, 足细胞与勃氏囊壁层细胞相连 肾小球过滤液在勃氏囊两层细胞之间的勃氏腔积累, 并流入肾小体肾小管 ( 尿液 ) urinary 端的近端小管 肾小球毛细血管腔与勃氏腔之间的肾小球过滤屏障共有 4 层, 其功能各有不同 (1) 内皮细胞腔面多糖包被 ( 糖萼 )glycocalyx 层,(2) 毛细血管内皮细胞层,, (3) 基底膜,(4) 上皮足细胞层 肾小球毛细血管内皮细胞被肾小球基底膜和一层足细胞突起几乎完全包被 肾小球中心血管内皮细胞处没有基底膜或足细胞, 但此处内皮细胞与平滑肌类的系膜细胞 mesangial cells 直接接触 血浆过滤发生在与系膜细胞所对的远端外周毛细血管壁, 此处有基底膜和足细胞 肾小球动脉毛细血管血管内皮细胞含有较大 70 nm 的开孔 fenestrations, 因而对水分子和其它小溶质包括蛋白质和其它大分子渗出毛细血管腔没有限制 此处内皮细胞的作用可能只是限制细胞如红细胞的流出 位于内皮细胞和足细胞突起之间的基底膜 basement membrane,, 将内皮细胞层与肾小球丛所有部位的细胞层所分离 基底膜有三层 : (1) 内层 lamina rara interna), (2) 后层 lamina densa,(3) 和外层 lamina rara externa 基底膜对于过滤障碍的通透性有重要贡献, 可限制大中溶质 (> 1 kda) 的通透 因为基底膜含硫酸乙酰肝素蛋白聚糖 heparan sulfate proteoglycans HSPG, 故而限制和浮点溶质的通透 Figure 33-3 A-G, Development of glomerulus and Bowman's capsule. H, The capillary lumen. The four major layers of the glomerular filtration barrier. I, Model of podocyte foot processes and slit membrane. The intracellular domain of nepr he diagram shows nephrin and other proteins of the slit diaphragm. (A-E modified from Ekblom P: In Seldin DW, Giebisch G: The Kidney, 2nd ed, pp New York: Raven Press, 1992; H modified from Kriz W, Kaissling B: In Seldin DW, Giebisch G [eds]: The Kidney: Physiology and Pathophysiology, 3rd ed, pp New York: Raven Press, 2000.)

8 足细胞 肾小体 ( 肾小球和勃氏囊 ) 的结构 II 足细胞突起内皮细胞胞浆基地膜球内系膜细胞 缝隙隔膜多糖包被 ( 糖萼 ) 内皮细胞孔缝隙隔膜的组成 勃氏腔 足细胞体 过滤障碍 毛细血管 多糖包被足胞突起毛细内皮肾小球基底膜 足细胞 Podocytes h 的交错突起覆盖于基地膜之上 交错突起之间是过滤缝隙 filtration slits; 交错突起之间有极薄的隔膜结构 - 缝隙隔膜 slit diaphragms - 相连 缝隙隔膜中有 4 14 nm 的孔道 荷负电的糖蛋白覆盖足细胞体 交错突起 以及缝隙隔膜 其所荷负电可限制较大阴离子的滤过 相邻足细胞跨膜蛋白 nephrin 和 NEPH1 的胞外结构域组成拉链形成缝隙隔膜 Podocin 及其它蛋白也参与缝隙隔膜的形成 这些蛋白质的胞内磷酸化酪氨酸结构模块可募集其它信号蛋白共同调控缝隙通透性 slit permeability 其中任何一种蛋白的遗传突变都可导致过滤障碍的泄露, 使得尿液中出现蛋白质如白蛋白 肾单元综合征 nephrotic syndrome 如 nephrin 的敲除导致先天性芬兰型的肾单元基质, 支持或固定肾小球毛细血管环 系膜细胞网络与传入和传出小动脉的平滑肌细胞相连通 基质连至球外系膜 extraglomerular mesangial 细胞 近球器 juxtaglomerular apparatus (JGA) 包括球外系膜细胞, 致密斑 macula densa 和颗粒 granular 细胞 致密斑 macula densa 是指粗升支和远端小管交界处的一组特化肾小管上皮细胞, 可于各自肾小球接触 致密斑细胞细胞和很大, 排列密集, 形成斑状结构 颗粒细胞传入小动脉壁的也叫近球或上皮样细胞, 是特化的平滑肌细胞, 合成储存释放肾素 renin 近球器 JGA 是复杂反馈通路的一部分调控肾脏血流 肾过滤率, 也间接调控 Na + 平衡和系统血压 Figure 33-3 A-G, Development of glomerulus and Bowman's capsule. H, The capillary lumen. The four major layers of the glomerular filtration barrier. I, Model of podocyte foot processes and slit membrane. The intracellular domain of nepr he diagram shows nephrin and other proteins of the slit diaphragm. (A-E modified from Ekblom P: In Seldin DW, Giebisch G: The Kidney, 2nd ed, pp New York: Raven Press, 1992; H modified from Kriz W, Kaissling B: In Seldin DW, Giebisch G [eds]: The Kidney: Physiology and Pathophysiology, 3rd ed, pp New York: Raven Press, 2000.) 交错突起

9 足细胞突起覆盖肾小球脉细血管网络 Glomerular capillaries covered by the foot processes of podocytes 足突起 主突起 SEM 显微成像显 示勃氏腔中肾小球 毛细血管 毛细血 管内皮细胞外表面 被足细胞交错突起 所覆盖 足细胞体 通过 腿 样结构 与足突起相连 二级突起 Figure 33-4 Glomerular capillaries covered by the foot processes of podocytes. This scanning electron micrograph shows a view of glomerular capillaries from the vantage point of Bowman's space. The outer surfaces of the capillary endothelial cells are covered by a layer of interdigitating foot processes of the podocytes. The podocyte cell body links to the foot processes by leg-like connections. (Courtesy of Don W. Fawcett.)

10 肾小球腔面展示内皮细胞窗孔 Inner aspect of glomerular capillaries, showing fenestrations of endothelial cells f 70 nm 扫描电镜 Figure 33-5 Inner aspect of glomerular capillaries, showing fenestrations of endothelial cells (arrows). This scanning electron micrograph shows a view of the glomerular capillary wall from the vantage point of the capillary lumen. Multiple fenestrations, each 70 nm in diameter, perforate the endothelial cells. (From Brenner BM: Brenner and Rector's The Kidney, 7th ed, vol 1, p 10. Philadelphia: Saunders, 2004.)

11 近端小管顶端和旁侧面质膜都被质膜得广泛折叠所放大 尤其是顶端膜即腔面质膜是典型的毛刷边沿膜结构 这与近端小管将肾小球过滤液打不冲吸收直接相关 与近端小管相比, 升支降支细袢 (tdlh, talh) 细胞则线粒体较少, 质膜放大不明显 升支粗袢 TAL 上皮细胞旁侧面质膜折叠广泛, 线粒体含量丰富 这些细胞与髓质高渗间质液形成密切相关 近端曲小管 PCT 近端直小管 PST 降支细袢 tdlh 升支细袢 talh 升支粗袢 TAL 肾单元不同部位的肾小管 Structure of tubule cells along the nephron 远端曲小管 DCT 连接管 CNT 闰管细胞初始收集管 ICT 闰管细胞皮质收集管 CCT 外髓收集管 OMCD 内髓收集管 IMCD 非常高 Figure 33-6 Structure of tubule cells along the nephron. Because of the variability among tubule segments, the cross sections of the tubule are not to scale. 贝氏管 连接管 CNT 含 CNT 细胞和闰 intercalated 管细胞 连接 CNT 管细胞合成和释放丝氨酸蛋白水解酶 kallikrein, 调控管道顶端跨膜通道和转运蛋白初始收集管 ICT 和皮质收集管 CCT 皆含收集管细胞和闰管细胞. 闰管细胞可占收集管数量 1/3, 无中心纤毛 闰管细胞 A (α) 分泌 H + 重吸收 K +,, 闰管细胞 B (β) 分泌 HCO3-. 主细胞或收集管细胞占收集管 (ICT 和 CCT) 细胞 2/3 主细胞相比线粒体少, 旁侧面质膜折叠不广泛, 顶端面含有一个中心线没纤毛 主细胞重吸收 Na + 和 Cl, 分泌 K + 髓质收集管 MCD 只有一种细胞, 高度向髓质乳突方向逐渐增大 细胞参与电解质及激素调控的水和尿素转运 贝氏管细胞变得

12 肾小管分段 Tubule Segment Proximal convoluted tubule Proximal straight tubule 肾单元中肾小管的分段 Tubule Segments of the Nephron Thin descending limb of loop of Henle Thin ascending limb of loop of Henle Thick ascending limb of loop of Henle Distal convoluted tubule Connecting tubule Initial collecting tubule Cortical collecting tubule Outer medullary collecting duct Inner medullary collecting duct 肾小管紧密连接的连接度从近端小管向收集管逐渐增加 在比较渗漏的近端小管, 紧密连接复合体较浅, 在冷冻电镜只显示一条跨膜蛋白带 但是在收集管, 紧密连接比较深, 有多条跨膜蛋白带组成 跨膜蛋白条带少则紧密连接的电阻低, 溶质通透性高 ; 条带多则电阻高, 通透性低 相邻肾小管之间的间隙连接存在于某些细胞 近端小馆细胞之间存在间歇连接, 但是连接管和收集管中不同细胞类型之间不存在间隙连接 缩写 Abbreviation PCT 近端曲小管 PST 近端直小管 tdlh 降支细亨氏袢 talh 升支细亨氏袢 TAL 升支粗亨氏袢 DCT 远端曲小管 CNT 连接 ( 小 ) 管 ICT 初始收集 ( 小 ) 管 CCT 皮质收集 ( 小 ) 管 OMCD 外髓收集管 IMCD 内髓收集管

13 肾单元将血浆过滤, 在肾小管重吸收, 和分泌溶质 The nephron forms an ultrafiltrate of the blood plasma and then selectively reabsorbs the tubule fluid or secretes solutes into it 与体内其它地方一样,Starling 力控制液体跨越肾小球毛细血管壁形成净过滤液 在肾小球处将血浆过滤至与近端小管相通的勃氏腔, 而不是细胞间质 肾小管的主要功能是将在肾小球率过液进行和溶质大部予以重收集 如果肾脏没有在肾小管的重新收集, 则肾脏在半小时皆可将所有血浆完全排出体外 肾小球滤过液吸收的大部发生在近端肾小管, 重吸收 NaCl, NaHCO 3, 及被过滤的营养成分如葡萄糖和氨基酸, 二价离子如钙 磷酸根 硫酸根, 和水分子 近端肾小管分泌 NH 4 + 和各种内源性和外源性溶质至管腔之中 亨氏袢各段 (tdlh, talh, TAL ) 参与形成浓缩或稀释尿液 亨氏袢将 NaCl 泵入肾脏髓质的细胞间质但水分子不随之转运, 导致间质液高渗 下游髓质收集管利用这种高渗间质通过渗透压梯度控制水分子是否进入间质 人体只有约 15% 的肾单元, 即近球肾单元, 其亨氏袢较长进入髓质乳突尖 但这部分肾单元对于在肾乳突处生成渗透压梯度非常重要 ; 这种渗透压梯度对于将水分子从髓质收集管管腔转运出来极其关键 正是因为收集管对水分的吸收, 收集管中尿液的渗透压大大低于血浆 升支粗袢 TAL 细胞分泌 Tamm-Horsfall 糖蛋白 (THP), 又叫尿调素 uromodulin 正常人每天排泄 mg THP 进入尿液 THP 与白蛋白 (< 20 mg/day) 是正常尿液中的主要蛋白质 THP 可与某些类型的大肠杆菌结合, 对于尿路系统的内在免疫反应和保持无菌状态至关重要 THP 也可降低钙晶体的形成, 避免形成尿结石 远端肾小管和收集管对于盐水排泄的精确控制非常重要 虽然只有小部分的肾小球过滤液可到达远端肾单元成份, 但是这些管段可分泌几种激素 ( 醛固酮 aldosterone, 精氨酸加压素 vasopressin), 这些激素调控电解质和水分子排泄

14 近球器 JGA 升支粗袢中与肾小球接触之处 A region where each thick ascending limb contacts its glomerulus 近球器 JGA 具有两种重要作用 当到达肾单元致密斑的液体和 NaCl r 增加后, 相应扥肾单元肾小球过滤率降低 这就是所谓的额肾小管 - 肾小球反馈 tubuloglomerular feedback 当灌流各种入球小动脉的肾动脉血压降低时, 入球小动脉压力感受器所感受导的对小动脉壁的牵拉减少, 导致相邻的颗粒细胞分泌并进入系统循环的肾素减少 肾素 - 血管紧张素 - 醛固酮调控轴 renin-angiotensin-aldosterone axis 对于系统动脉压的 ystemic arterial blood pressure 的长期调控非常重要 肾脏交感神经调控肾血流 肾小球过滤率和肾小管的重吸收 Sympathetic nerve fibers to the kidney regulate renal blood flow, glomerular filtration, and tubule reabsorption 肾脏的自主神经支配只有交感神经而没有副交感神经 交感神经来自于腹腔神经丛 celiac plexus, 与动脉血管并行至肾脏 交感神经的膨体释放 NE 和多巴胺至血管系统 ( 肾动脉及入球 出球小动脉 ) 平滑肌附近的疏松结蹄组织和近端肾小管 交感刺激对于肾脏的作用有三 儿茶酚胺刺激血管收缩 儿茶酚胺刺激近端小管对 Na + 的重吸收 近球器 JGA 颗粒细胞附近密集交感神经末梢的存在, 交感神经活动增加刺激肾素分泌 肾脏输入神经或感觉神经是有髓鞘神经纤维 这些神经纤维传导来自于肾脏压力感受器和化学感受器的神经冲动 血液灌流增加刺激小叶间动脉和入球小动脉压力感受器 肾脏缺血和间质液离子成份的异常刺激肾盂 renal pelvis. 化学感受器 胞外 K + 和 H + 刺激肾盂化学感受器, 增加毛细血管血流量 肾脏作为内分泌器官生成肾素 维生素 D 红细胞生成素 前列腺素及缓激肽 The kidneys, as endocrine organs, produce renin, 1,25-dihydroxyvitamin D, erythropoietin, prostaglandins, and bradykinin 近球器颗粒细胞合成肾素 近端小管可将血液循环中的 25-hydroxyvitamin D 转换为活性状态的 1,25- dihydroxyvitamin D, 调控小肠 肾脏 骨头的钙磷代谢 当局部组织氧分压降低时, 肾脏皮质和外髓质间质的成纤维类细胞分泌红细胞生成素 erythropoietin (EPO) EPO 刺激红细胞生成 肾衰竭时 EPO 分泌降低导致贫血, 可通过注射 EPO 予以缓解 肾脏释放控制血液循环的前列腺素, 激肽 kinins,, 旁分泌物质 这些物质一般是舒张血管的, 贫血时可保护肾脏 肾小管细胞可分泌血管紧张素 缓激肽 camp, ATP, 在小管腔调控下游肾单元的功能

15 测量肾脏转运与清除率 Measuring Renal Clearance and Transport 动脉血浆浓度 x 肾血浆血流 动脉输入 静脉输出 静脉血浆浓度 x 肾血浆血流 尿的输出 尿浓度 x 尿输出率 Figure 33-7 Solute mass balance in the kidney.

16 物质尿排泄的影响因素 Factors contributing to the net urinary excretion of a substance 入球小动脉肾小球毛细血管勃氏腔滤过总量重吸收量分泌量排泄量 出球小动脉 有些物质经过肾脏一次即可被完全从血浆中清除 如对氨基马尿酸如 para-aminohippurate (PAH) 血浆中某些物质可被完全过滤 ( 血浆浓度与勃氏腔浓度相等 ), 且肾小管不吸收 分泌 合成 降解 积累该物质, 则该物质肾小球滤过速率等于尿排泄速率 菊糖即是此类物质 肾小管外毛细血管 肾小管管腔肾脏静脉 Figure 33-8 Factors contributing to the net urinary excretion of a substance.

17 单个肾单元滤过率 吸收 分泌的显微测量方法 Microscopic techniques make it possible to measure single-nephron rates of filtration, absorption, and secretion A. 肾小管微穿刺 B. 肾小管的停流微灌流 C. 肾小管持续性微灌流 D. 分离肾小管的灌流 Figure 33-9 Methods for studying renal function in the research laboratory.

18 单个肾单元肾小球过滤率的测量 Measurement of single-nephron glomerular filtration rate 菊糖血浆 P 浓度 入球小动脉 出球小动脉 勃氏腔 因菊糖可自由滤过, 勃氏腔浓度等于血浆浓度 近端小管重吸收 2/3 的滤过水 导致聚糖浓度是初始浓度的三倍 单个肾单元球过滤率 SNGFR 收集率菊糖肾小管液 TF 浓度 收集电极 单个肾单元求过滤率 Figure Measurement of single-nephron glomerular filtration rate. Data are for the rat.

19 输尿管和膀胱 输尿管和膀胱 Anatomy of the ureters and bladder 记录电极 平滑肌动作电位 膀胱底 膀胱三角 Vm 输尿管开口 刺激 阈值 Figure A and B, Anatomy of the ureters and bladder. In B, ureteral smooth muscle cells generally have a resting membrane potential of -60 mv, mainly determined by a high K+ membrane permeability. Na+ channels speed the upstroke of the action potential, although Ca2+ channels are mainly responsible for the action potential.

20 尿道括约肌 Urethral Sphincters 特点 Characteristic 内括约肌 Internal Sphincter 外括约肌 External Sphincter 肌肉类型 Type of muscle 平滑肌 Smooth 骨骼肌 Skeletal 神经支配 Nerve 胃下神经 Hypogastric 阴部神经 Pudendal 神经类别 Nature of innervation 自主神经 Autonomic 躯体神经 Somatic

21 膀胱的自主和躯体神经支配 Autonomic and somatic innervation of the bladder 上肾腹肠 G 腔系 G 膜 G 主动脉肾 G 交感神经干 腰部内脏 N 骶部内脏 N 下肠系膜 G 交感节前 N 副交感节后 N 副交感节前 N 副交感节后 N 躯体感觉 N 躯体运动 N 上胃下神经丛胃下神经丛 骶神经丛 盆腔内脏神经阴部神经 下胃下盆腔丛 Figure Autonomic and somatic innervation of the bladder. 膀胱内括约肌丛外括约肌丛

22 膀胱内压图与排尿反应 A cystometrogram 随意排尿压力波 膀胱逐渐排空 膀胱内压 充盈 被动张力基础膀胱内压 Figure A cystometrogram. 膀胱容量

23 入球小动脉 肾小球毛细血管 勃氏腔 菊糖的清除可表示肾小球滤过率 The Clearance of inulin is a measure of GFR 出球小动脉 菊糖滤过量 无重吸收 无分泌 排泄量等于滤过量 尽管菊糖清除率可作为肾小球滤过率的可靠方法, 但是并不适合于应用于临床 首先菊糖是外源物, 需要进行静脉注射才能维持稳定血浆浓度 另外分析血浆或尿液中菊糖浓度较为复杂, 不适合日常临床实验室使用 标准 70 公斤男人正常肾小球滤过率 GFR 是 125 ml/min GFR 大小与体表面积成正比 标准 70 公斤男人体表面积是 1.73 m 2, 故男人正常 GFR 是 125 ml/min / 1.73 m 2 女人是 110 ml/min per 1.73 m 2 Figure 34-1 Clearance of insulin.

24 肌酸酐清除率 临床肾小球滤过率检测 The clearance of creatinine is a useful clinical index of GFR = 1 mg / min 通过经脉注射 GFR 标记物打的问题如果使用具有菊糖类似性质的内源物质即可 肌酸酐 Creatinine 正是这麽一个分子 肌酸酐清除率 creatinine clearance (C Cr ) 可用于估测人的 肾小管分泌少量肌酸酐, 者可导致对 GFR 高估 ~20% 临床实践中检测 dc Cr 非常方便和可靠, 不需要向病人注射任何东西 只需要获得病人静脉血和尿并检测器肌酸酐浓度即可计算出 Ccr 虽然这可能会高估人的 GFR, 但是对于病人 GFR 的相对变化来说, 还是非常有用的 Figure 34-2 Dependence of plasma creatinine and blood urea nitrogen on the GFR. In the steady state, the amount of creatinine appearing in the urine per day (UCr V) equals the production rate. Because all filtered creatinine (PCr CCr) appears in the urine, (PCr CCr) equals (UCr V), which is constant. Thus, PCr must increase as CCr (i.e., GFR) decreases, and vice versa. If we assume that the kidney handles urea in the same way that it handles inulin, then a plot of blood urea nitrogen versus GFR will have the same shape as that of creatinine concentration versus GFR.

25 肾小球过滤屏障的通透选择性 Permselectivity of the Glomerular Barrier 溶质 Substance MWt. (Da) Mol. Radius (nm) Filtrate (UF X /P X ) Na K Cl H 2 O Urea Glucose Sucrose Polyethylene glycol 1, Inulin 5, Lysozyme 14, Myoglobin 16, Lactoglobulin 36, Egg albumin 43, Bence Jones protein 44, Hemoglobin 68, Serum albumin 69, <0.01 *The effective molecular radius is the Einstein-Stokes radius, which is the radius of a sphere that diffuses at the same rate as the substance under study. Data from Pitts RF: Physiology of the Kidney and Body Fluids, 3rd ed. Chicago: Year Book, 1974.

26 分子大小和电荷影响溶质的肾小球滤过率 Molecular size and electrical charge determine the filterability of solutes across the glomerular filtration barrier 荷正电葡聚糖 中性葡聚糖 荷负电葡聚糖 肾毒性血浆肾炎 正常肾 Figure 34-4 Clearance ratios of dextrans. (Data from Brenner BM, Hostetter TH, Humes HD: N Engl J Med 1978; 298: )

27 静水压 胶体压对肾小球过滤的影响 Hydrostatic pressure in glomerular capillaries favors glomerular ultrafiltration, whereas oncotic pressure in capillaries and hydrostatic pressure in Bowman s space oppose it 常数 K f 是肾小球毛细血管静水压导 hydraulic conductivity (L p ) 与有效过滤表面积 (S f ) 之积 因为 Lp 与 Sf 实验上难于确定, 故而使用 K f 肾小球过滤常数 K f 比系统循环毛细血管床 K f 总和还要大一个数量级 常数 K f 差别导致血液过滤的巨大差别, 肾脏每天过滤约 180 L ( 肾血流量是心输出量的 20%), 而系统循环毛细血管床小动脉端的过滤量总和是每天约 20 L ( 心输出量的 ~80%)

28 静水压 胶体压对肾小球过滤的影响 Hydrostatic pressure in glomerular capillaries favors glomerular ultrafiltration, whereas oncotic pressure in capillaries and hydrostatic pressure in Bowman s space oppose it 入球小动脉 勃氏腔 出球小动脉 两力驱动过滤 两力对抗过滤 驱动力 肾小球超滤依赖于超滤系数 K f 与 Starling 力之积 驱动超滤的力是肾小球毛细血管静水压 P GC, 勃氏腔胶体压 (π BS ) 对抗超滤的是勃氏腔静水压 (P BS ) 和肾小球毛细血管胶体压 (π GC ) 故而 (P GC, 对抗力 π BS ), 驱动超滤, (P BS, π GC ) 对抗超滤 入球小动脉出球小动脉 Figure 34-5 A-C, Glomerular ultrafiltration. In B, the oncotic pressure of the glomerular capillary (πgc), which starts off at the value of normal arterial blood, rises as ultrafiltration removes fluid from the capillary. In C, PUF is the net driving force favoring ultrafiltration.

29 肾血浆流量 Renal blood flow (RBF) 肾血流量 Renal blood flow (RBF) 为心输出量的 1 / 5, 即是 1 L/min 成人血细胞压积 0.4, 故肾血浆流 (RPF) 为 :1 L x 0.6 = 300 ml / min

30 肾小球血浆刘较低时, 过滤平衡 filtration equilibrium 发生肾小球毛细血管中段 后段不再发生过滤 血浆流增加导正常水平后, 经超滤力 P UF 轮廓向后段大幅扩展 ; 平衡点远超毛细血管末端 过滤 filtration disequilibrium 的出现是因为血浆流过大超过了毛细血管的过滤和移出液体和增加胶体压的能力 结果 π GC 延毛细血管增加缓慢 当肾小球血浆流从低向高增加时, 过滤平衡点逐渐向远端即出球小动脉方向移动 这样移动的结果, 超滤力 P UF 保持高位 ; 更多的肾小球毛细血馆参与过滤, 增加过滤或超滤的总表面积 较低血浆流时远端浪费的毛细血管过滤装臵也得到利用, 视为高血浆流所保留的后备 随着血浆流的更高增加, 肾小球胶体压 π GC 轮廓被扩展更多, 超滤能力 P UF 在每段毛细血管都在比较高的位臵 肾小球血浆流增加导致 GFR 的增加 Increased glomerular plasma flow leads to an increase in GFR 入球小动脉 对抗力 对抗力 对抗力 驱动力 驱动力 驱动力 GFR FF 出球小动脉 Figure 34-6 Dependence of the GFR on plasma flow. 肾血浆流 (RPF) 肾血浆流 (RPF) 单个肾单元肾小球过滤率 SNGFR 是毛细血管每个过滤事件之和 因而 SNGFR 与途中黄色部分 ( 超滤力 P UF 与有效长度之积 ) 成正比 黄色部分面积随着血浆流的增加而增加,SNGFR 也随着血浆流的增加而非线性增加 与正常血浆流情况相比, 双肾总 GFR 随着肾血浆流 RPF 的增加较小 但是血浆流降低后却大幅降低肾 GFR 实际上也确实如此, 临床上肾脏灌流降低后, GFR 大幅降低 GFR 与 RPF 之间的关系也可以用过滤分数 filtration fraction (FF), 来表示 : 过滤液体积与馆留学将体积之比 正常 GFR 是 ~125 ml/min 而正常 RPF 是 ~600 ml/min 时, 正常 FF 则是, ~0.2 因为 RPF 高时 GFR 达到饱和,RPL 逐渐升高后 FF 逐渐降低

31 入 出球小动脉阻力调节 GPF 和 GFR Afferent and efferent arteriolar resistances control both glomerular plasma flow and GFR 入球和出球小动脉压的大幅下降 血压 肾小球毛细血管血压相对较高, 而肾小管周围毛细血管血压较低 入球和出球小动脉的收缩和舒张可高度选择性敏感调控肾小球毛细血管静水压和肾小球过滤 肾小球毛细血管静水压较高 FF Figure 34-7 Pressure profile along the renal vasculature.

32 入 出球动脉阻力 ( 总阻力不变 ) 对毛细血管压影响 肾动脉压 入球 阻力 阻力相等 入球阻力高 出球阻力高 小球毛细压管周毛细压 理想情况下保持肾小球总阻力不变, 即肾小球血浆流不变时, 增加或降低入球阻力或出球阻力 ( 收缩入球动脉舒张出球动脉 ) 则 P GC 降低 相反, 舒张入球动脉收缩出球脉 ( 降低入球阻力增加出球阻力 ) 则导致 P GC 的升高 从这些理想情况下肾小球毛细血管血压 P GC 的变化, 可预测增加入球阻力则降低 GFR, 增加出球阻力则 GFR 增加 但实际生理情况下一半不易保持肾小球总阻力不变 肾小球小动脉阻力变化可不依赖于肾小球毛细血管压而导致肾小球过滤率 GFR 的变化 Figure 34-8 Role of afferent and efferent arteriolar resistance on pressure and flows. In A, the sum of afferent and efferent arteriolar resistance is always 2, whereas in B and C, the total resistance changes. 出球 阻力

33 入球效动脉阻力增加对毛细血管过滤率 GFR 影响 肾小球过滤率 肾血浆流 肾小球过滤率 GFR 因肾小球毛细血管压和肾血浆流的共同降低而降低 小动脉压相对变化 Figure 34-8 Role of afferent and efferent arteriolar resistance on pressure and flows. In A, the sum of afferent and efferent arteriolar resistance is always 2, whereas in B and C, the total resistance changes.

34 入球效动脉阻力增加对毛细血管过滤率 GFR 影响 肾小球过滤率 肾小球过滤率 肾血浆流 肾小球过滤率 GFR 因肾小球毛细血管压增加占主流而增加 小动脉压相对变化 肾小球过滤率 GFR 因肾血浆流降低占主流而降低 Figure 34-8 Role of afferent and efferent arteriolar resistance on pressure and flows. In A, the sum of afferent and efferent arteriolar resistance is always 2, whereas in B and C, the total resistance changes.

35 肾小球小动脉阻力对过滤率 GFR 的影响 1/ 交感神经刺激或 ANGII 刺激导致入 出球动脉同时收缩, 入 出球阻力皆增加 肾血浆流 RPF 降低 增加的入球阻力和出球阻力对 GFR 的影响相互抵消, 故尽管肾血浆流 RPF 降低, 肾小球过滤率 GFR 保持不变 2/ 供肾者肾脏切除后入球阻力降低 肾血浆流 RPF 增加, 结果剩余肾脏的 GFR 增加 1 倍 3/ 充血性心衰时肾灌流降低, 但因不明机制, 舒张血管的前列腺素 (PGE 2, PGI 2 ) 大量增加 病人 GFR 的维持极大地依赖于前列腺素所介导入球小动脉舒张 抑制前列腺素合成的抑制剂 (NSAID) 常导致病人 GFR 急性降低 4/ 充血性心衰病人肾脏灌流降低 病人内源性血管紧张素 angiotensin 含量增加, 导致出球小动脉收缩 肾小球毛细血管压 P GC 增加, 这样 GFR 可保持正常 血管紧张素转化酶抑制剂 (ACE-I) 在这些病人可导致肾小球过滤率 GFR 急性降低 [ 因 ACE-I 作用, 血管紧张素降低, 出球小动脉阻力降低, P GC 降低, 故 GFR 急性降低 ]

36 在标准系统毛细血管床动脉端过滤 静脉端吸收 In standard systemic capillaries, Starling forces favor filtration at the arteriolar end and absorption at the venular end 黄线显示理想化毛细血管 (Pc) 和间质液 (Pif) 静水压 二者之差为净静水压 红线显示理想化毛细血管 (πc) 和间质液 (πif) 胶体渗透压 二者之差净渗透压 P C π if P if π C 净过滤压为 : (Pc - Pif) - σ(πc - πif) 净过滤出毛细血管 净过滤 净回收 净吸收回毛细血管 Figure 20-9 Starling forces along a capillary. In A, the yellow lines are idealized profiles of capillary (Pc) and interstitial (Pif) hydrostatic pressures. Red lines are idealized capillary (πc) and interstitial (πif) colloid osmotic pressures. In B, the net filtration pressure is (Pc - Pif) - σ(πc - πif).

37 入球小动脉 肾小管周毛细血管回收重吸收液体 Peritubular capillaries retrieve reabsorbed fluid 出球小动脉 50-(25+10) 肾小球血浆流 47-(35+10) 肾小球毛细血管与标准毛细血管动脉端类似 :Starling 力趋于过滤 ( 黄色区 ) 勃氏腔 35+8-(20+6) 管周毛细血管净吸收力 25+8-(15+6) 头 管周毛细血管与标准静脉端类似, Starling 力趋于吸收 ( 褐色区 ) 管周毛细血管 尾 Figure 34-9 Starling forces along the peritubular capillaries. See text for discussion.

38 血流动力学变化对管周毛细血管重吸收影响 Effects of hemodynamic changes on fluid reabsorption by the peritubular capillaries 血容量增加 入球小动脉阻力 球过滤率 肾血浆流 过滤比例管周毛细血管胶体压管周毛细血管静水压 管周毛细血管液体摄取 Figure Effect of volume expansion on fluid uptake by the peritubular capillaries.

39 自调节的肌源反应 Myogenic Response: 肾脏自我调节肾血流 RBF 肾动脉压升高导致成比例入球小动脉祖力增加 奇迹之是动脉压升高导致入球小动脉比收到牵张, 激活血管平滑机细胞牵拉敏感的非选择性阳离子通道 细胞膜去极化导致电压门控钙离子通道开放, 钙离子内流刺激收缩 肾血流与肾小球过滤的调控 Control of Renal Blood Flow and Glomerular Filtration 自调节维持 RBF 和 GFR 较为恒定 : 肌源反应入球小动脉阻力 血管阻力 肾血流量 球过滤率 肾动脉压 出球小动脉阻力 mm Hg Figure Autoregulation of renal blood flow and GFR. (Data from Arendshorst WJ, Finn WF, Gottschalk CW: Am J Physiol 1975; 228: )

40 肾血流与肾小球过滤的调控 Control of Renal Blood Flow and Glomerular Filtration 自调节维持 RBF 和 GFR 较为恒定 : 管 - 球反馈 TGF 高蛋白饮食因某种原因增加近端小管对 NaCl 重吸收, 致密斑腔面 [NaCl] 浓度降低 Henle 环流量即 GFR 增加才可升高致密斑腔面 [NaCl] 触发 TGF 故高蛋白饮食降低 TGF 敏感性 TGF-desensitizing agents: ANP NO camp Prostaglandin I2 High-protein diet TGF -sensitizing agents: Adenosine; Prostaglandin E2; Thromboxane; Hydroxyeicosatetraenoic acid; Angiotensin II 1/ 肾动脉压增加导致肾小球毛细血管压增加,RPF 和 GFR. 的增加致 2/ 增加的 IGFR 导致近端小管管腔面 Na + 和 Cl 的增加, 最终导致近球器致密斑细胞腔面 Na + 密和 Cl 的增加斑 3/ 致密斑细胞顶端质膜在 Na/K/Cl 共转运蛋白作用下, 胞浆浓度相应增加 实际上阻断 Na/K/Cl 共转运也阻断 TGF 细 4/ 胞浆 [Cl ] i 的增加后在旁侧面质膜 Cl 通道开放后质膜去极化胞 5/ 质膜去极化导致质膜电压门控钙通道开放, 钙内流增加后胞浆钙浓度增加 6/ 胞浆钙增加后刺激致密斑细胞释放活性物质腺苷 adenosine 和 ATP, 后者水解后也产生腺苷 7/ 腺苷与入球小动脉血管平滑肌细胞质膜 A 1 受体结合刺激其收缩 8/ 入球小动脉阻力增加后降低 GFR, 负反馈调节初始 GFR 的升高 Figure Tubuloglomerular feedback. (Data from B modified from Navar LG: Adv Physiol Educ 1998; 20:S221-S235.)

41 人体水的摄入和排出平衡 Input and Output of Water 摄入 INPUT 来源 Source Amount (ml) 饮料水 Ingested fluids 1200 食物水 Ingested food 1000 代谢水 Metabolism 300 合计 Total 2500 排出 OUTPUT 途径 Route Amount (ml) 尿液 Urine 1500 粪便 Feces 100 皮肤汗液 Skin/sweat 550 呼出水汽 Exhaled air 350 合计 Total 2500 (Data from Valtin H: Renal Dysfunction: Mechanisms Involved in Flud and Solute Imbalance, p 21. Boston: Little, Brown, 1979.)

42 肾小管对水的吸收 Tubule fluid is isosmotic in the proximal tubule, becomes dilute in the loop of Henle, and then either remains dilute or becomes concentrated by the end of the collecting duct Water Transport by Different Segments of the Nephron 1/ AVP level 2/ H 2 O permeability 3/ H 2 O absorption 近端小管亨氏袢远端管 皮质髓质收集管收集管尿液 抗利尿 Antidiuresis 小管液 Osm / 血浆 Osm 水利尿 Water diuresis Figure 38-1 Relative osmolality of the tubule fluid along the nephron. Plotted on the y-axis is the ratio of the osmolality of the tubule fluid (TF) to the osmolality of the plasma (P); plotted on the x-axis is a representation of distance along the nephron. The red record is the profile of relative osmolality (i.e., TF/Posmolality) for water restriction, whereas the blue record is the profile for high water intake. (Data from Gottschalk CW: Physiologist 1961; 4:33-55.)

43 1/ 亨氏袢主要功能是将 NaCl 比水分子更有效地从管腔移至髓质间质 通过将管腔 NaCl 与水分离, 亨氏袢直接参与尿液稀释 反之因升支粗袢 TAL 将 NaCl 堆积于髓质间质导致尿液低渗, 亨氏袢间接参与尿液浓缩 2/ 无论是抗利尿还是水利尿, 间质渗透压从皮层至髓质突间逐步增加 ( 皮髓渗透压梯 ) 度 二者区别是抗利尿时间质液最大渗透压 1200 mosm, 水利尿时 500 mosm 3/ 因 NaCl 从不透水升支粗袢 TAL 移出, 两种情况下管腔液在升支粗袢末端相对皮层间质液都低渗 但升支粗袢 TAL 之后, 管腔渗透压有显著差别 抗利尿时管腔液从初始收集管 ICT 开始直至肾单元末端被逐渐浓缩 水利尿时管液低渗在管腔液从远端曲小管直到收集管末端变得逐渐更低渗, 这些不透水管道继续摄取 NaCl 抗利尿时初始 皮质 外髓 内髓收集管 ICT, CCT, OMCD, IMCD 管液与间质液达一定渗透压平衡 但水利尿时不能 这一渗透压平衡的显著差别在于精氨酸血管加压素 AVP 的作用,AVP 增加这些收集管对水分子的通透性 肾髓质高渗间质液 水通透 水通透 NKCC2 NKCC2 1/ 升支粗袢 TAL 主动穿胞运输 : 顶端质膜转运 Na + / Cl 通过 Na/K/Cl 共转运 NKCC2, 基底面质膜通过 Na-K 泵和 Cl 通道 胞旁运输 : 腔面为正的跨上皮压驱动 Na + 从腔面跨紧 Figure 38-2 Nephron and interstitial osmolalities. A, Water restriction (antidiuresis). B, High water intake (water diuresis). The numbers in boxes are osmolalities (mosm) along the lumen of the nephron and along the corticomedullary axis of the interstitium. The outflow of blood from the vasa recta is greater than the inflow, a finding reflecting the uptake of water reabsorbed from the collecting ducts. 水通透 密连接至间质面 二者共同使 TAL 产生单次效应的渗透压差 :200 mosm 2/ 升支细袢 talh 被动转运 : 管腔 NaCl 浓度大大超过内髓间质,NaCl 被被动重吸收 升支细袢氯离子通道 ClC-K1 对于 NaCl 的被动重吸收至关重要 3/ 近球肾单元的降支细袢浓缩腔面 NaCl:(a) 降支细袢 tdlh 水通透性高 (AQP1),(b) 降支细袢 tdlh 对 NaCl 不通透, 对尿素有限通透 (UT-A2), (c) 内髓间质极高浓度的 [NaCl] 和 [urea]

44 逆流作用原理 X 逆流放大装臵 countercurrent multiplier Simplifications of the Countercurrent-Multiplier Model 管中液前行转运得差 200 管中液前行转运得差 200 管中液前行转运得差 200 管中液前行转运得差 200 与收集管中平衡 Figure 38-3 Stepwise generation of a high interstitial osmolality by a countercurrent multiplier. This example illustrates in a stepwise fashion how a countercurrent-multiplier system in the loop of Henle increases the osmolality of the medullary interstitium. Heavy boundaries of ascending limb and early DCT indicate that these nephron segments are rather impermeable to water, even in the presence of AVP. The numbers refer to the osmolality (mosm) of tubule fluid and interstitium. The top panel shows the starting condition (step 0), with isosmotic fluid ( 300 mosm) throughout the ascending and descending limbs and in the interstitium. Each cycle comprises two steps. Step 1 is the "single effect": NaCl transport from the lumen of the ascending limb to the interstitium, which instantaneously equilibrates with the lumen of the descending limb (steps 1, 3, 5, and 7). Step 2 is an "axial shift" of tubule fluid along the loop of Henle (steps 2, 4, and 6), with an instantaneous equilibration between the lumen of the descending limb and the interstitium. Beginning with the conditions in step 0, the first single effect is NaCl absorption across the rather water-impermeable ascending limb. At each level, we assume that this single effect creates a 200-mOsm difference between the ascending limb (which is water impermeable) and a second compartment: the combination of the interstitium and descending limb (which is water permeable). Thus, the osmolality of the ascending limb falls to 200 mosm, whereas the osmolality of the interstitium and descending limb rise to 400 mosm (step 1). The shift of new isosmotic fluid ( 300 mosm) from the proximal tubule in the cortex into the descending limb pushes the column of tubule fluid along the loop of Henle, thus decreasing osmolality at the top of the descending limb and increasing osmolality at the bottom of the ascending limb. Through instantaneous equilibration, the interstitium-with an assumed negligible volume-acquires the osmolality of the descending limb, thereby diluting the top of the interstitium (step 2). A second cycle starts with net NaCl transport out of the ascending limb (step 3), again generating an osmotic gradient of 200 mosm-at each transverse level-between the ascending limb on the one hand and the interstitium and descending limb on the other. After the axial shift of tubule fluid and instantaneous equilibration of the descending limb with the interstitium (step 4), osmolality at the bottom of the ascending limb exceeds that of the preceding cycle. With successive cycles, interstitial osmolality at tip of the loop of Henle rises progressively from 300 (step 0) to 400 (step 1) to 500 (step 3) to 550 (step 5) and then to 600 (step 7). Thus, in this example, the kidney establishes a longitudinal osmotic gradient of 300 mosm from the cortex (300 mosm) to the papilla (600 mosm) by iterating (i.e., multiplying) a single effect that is capable of generating a transepithelial osmotic gradient of only 200 mosm. Step 7A adds the collecting duct and shows the final event of urine concentration: allowing the fluid in the collecting duct to equilibrate osmotically with the hyperosmotic interstitium, producing a concentrated urine. (Based on a model by Pitts RF: Physiology of the Kidney and Body Fluids. Chicago, Year Book, 1974.)

45 间质 Na + Cl - 尿素浓度沿皮质髓质轴变化 Concentration profiles of Na +, Cl -, and urea along the corticomedullary axis 间质 [Na + ] [Cl ], [urea] 浓度从皮质到髓乳突逐渐升高 外髓间质 [Na + ] [Cl ] 突然升高是因升支粗袢 TAL 主动将 NaCl 泵出管腔, 致间质液高渗 尿素在最外侧外髓对间质液高渗贡献不大,[urea] 浓度从外髓中部才开始升高 髓乳突尖尿素和 NaCl 对间质液高渗各贡献一半 尿素浓度在此处迅速升高是由收集管特定的水 尿素通透性所决定的 内髓乳突尖处间质液 [Na + ] [Cl ] 浓度皆达 300 mm, 而管腔 [Na + ] 和 [Cl ] 均超过 300 mm,, 为升支细袢提供 [Na + ] [Cl ] 穿胞重吸收的浓度梯度差 因升支细袢处尿素浓度梯度差, 和升支细袢比降支细袢对尿素更通透, 尿素进入升支细袢 尿素进入升支细袢部分抵消 NaCl. 重吸收所产生渗透压差 尽管升支细袢和粗袢对 NaCl 转运机制不同, 所产生跨膜浓度梯度也有差别, 但最后结果都导致升袢管腔渗透压总是低于间质渗透压 Figure 38-4 Concentration profiles of Na+, Cl-, and urea along the corticomedullary axis. The data are from hydropenic dogs. (Data from Ullrich KJ, Kramer K, Boylan JW: Prog Cardiovasc Dis 1961; 3: )

46 肾脏尿素循环 The IMCD reabsorbs urea, producing high levels of urea in the interstitium of the inner medulla The kidney filters urea in the glomerulus and reabsorbs about half in the proximal tubule (step 1). In juxtamedullary nephrons, the tdlh and the talh secrete urea into the tubule lumen (step 2). Some urea reabsorption occurs along t hetal up through the CCT (step 3). Finally, the IMCD reabsorbs urea (step 4). The net effect is that the kidney excretes less urea into the urine than it filters. Depending on urine flow, the fractional excretion may be as low as ~15% (minimal urine flow) or as high as ~65% or more (maximal urine flow As the tubule fluid enters the TAL, the [urea] is several-fold higher than it is in the plasma because ~100% of the filtered load of urea remains, even though earlier nephron segments have reabsorbed water. All nephron segments from the TAL to the OMCD, inclusive, have low permeabilities to urea. In the presence of AVP, however, all segments from the ICT to the end of the nephron have high water permeabilities and continuously reabsorb fluid. As a result, luminal [urea] gradually rises, beginning at the ICT and reaching a concentration as much as 8-fold to 10-fold higher than that in blood plasma by the time the tubule fluid reaches the end of the OMCD. AVP As the tubule fluid enters the TAL, the [urea] is several-fold higher than it is in the plasma because ~100% of the filtered load of urea remains, even though earlie nephron segments have reabsorbed wate All nephron segments from the TAL to t OMCD, inclusive, have low permeabilit to urea. In the presence of AVP, howeve all segments from the ICT to the end of the nephron have high water permeabilities and continuously reabsorb fluid. As a result, luminal [urea] gradual rises, beginning at the ICT and reaching concentration as much as 8-fold to 10-fo higher than that in blood plasma by the time the tubule fluid reaches the end of t OMCD. The IMCD differs in an important way from the three upstream segments: Although AVP increases only water permeability in the ICT, CCT, and OMC AVP increases water and urea permeability in the IMCD. In the IMCD the high luminal [urea] and the high urea permeabilities of the apical membrane (v the urea transporter UT-A1; and basolateral membrane (via UT-A3) promote the outward facilitated diffusion of urea from the IMCD lumen, through t IMCD cells, and into the medullary interstitium (step 4). As a result, urea accumulates in the interstitium and contributes about half of the total osmolality in the deepest portion of the inner medulla. In addition, in the outer portion of the inner medulla, active urea reabsorption occurs via an Na/urea cotransporter in the apical membrane of the early IMCD. Because of the accumulation of urea in t inner medullary interstitium, [urea] is higher in the interstitium than it is in the lumen of the tdlh and talh of juxtamedullary (i.e., long-loop) nephron This concentration gradient drives urea into the tdlh via UT-A2 and into the talh via an unidentified transporter (ste 2). The secretion of urea into the tdlh and talh accounts for two important observations: First, more urea (i.e., a greater fraction of the filtered load) emerges from the talh than entered the tdlh. Second, as noted above, [urea] in the TAL is considerably higher than that in blood plasma. Figure 38-5 Urea recycling. Under conditions of water restriction (antidiuresis), the kidneys excrete 15% of the filtered urea. The numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The single red box indicates the fraction of the filtered load secreted by the talh, and the single brown box indicates the fraction of the filtered load carried away by the vasa recta. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. The values in the boxes are approximations.

47 A 肾脏对 Na + 的处理 100% 8% 3% 33% 0.4% Figure 35-2 Estimates of renal handling of Na+ along the nephron. The numbered yellow boxes indicate the absolute amount of Na+-as well as the fraction of the filtered load-that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen at these sites. The values in the boxes are approximations. PNa, plasma Na+ concentration; UNa, urine Na+ concentration.

48 B 100% 肾脏对葡萄糖的处理 2% 0% Figure 36-3 A to C, Glucose handling by the kidney. The yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.

49 C 肾脏对游离氨基酸的处理 100% 1% 0% Figure 36-5 A and B, Amino acid handling by the kidney. In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.

50 D 肾脏对寡肽的处理 100% 1% 0% Figure 36-6 A and B, Oligopeptide handling by the kidney. In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.

51 E 肾脏对蛋白质的处理 100% 1% Figure 36-7 A and B, Protein handling by the kidney. In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations.

52 F 肾脏对 Pi - 的处理 10% 100% 20% 10% Figure A and B, Phosphate handling by the kidney. In A, the numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. The values in the boxes are approximations. In B, the top cell illustrates reabsorption of divalent phosphate ( ), and the bottom cell illustrates the reabsorption of monovalent phosphate ( ). PCT, proximal convoluted tubule; PST, proximal straight tubule.

53 G 100% 35% 肾脏对 Ca 2+ 的处理 2% 10% 1% Figure A to D, Calcium handling by the kidney. In A, the numbered yellow boxes indicate the approximate fraction of the filtered load that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. The values in the boxes are approximations. AC, adenylyl cyclase; PCT, proximal convoluted tubule; PST, proximal straight tubule.

54 H 100% 肾脏对 Mg 2+ 的处理 15% 85% 5% Figure A to C, Magnesium handling by the kidney. In A, the numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The DCT, initial collecting tubule (ICT), cortical collecting tubule (CCT), outer medullary collecting duct (OMCD), and IMCD together reabsorb 10% of the filtered load. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.

55 I 肾脏对 K + 的处理 10% 100% 10% 100% 8% % 20% 20% 2% % Figure 37-5 K+ handling in superficial nephrons. In A and B, the numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb, whereas the red box in B indicates the fraction of the filtered load secreted by the ICT and CCT. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments.

56 J 100% 20% 肾脏对 HCO 3 - 的处理 4% 10% 0.01% Figure 39-3 Acid-base handling along the nephron. A, The numbered yellow boxes indicate the fraction of the filtered load absorbed by various nephron segments. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. B, The red boxes indicate the moieties of acid secretion associated with either the formation of titratable acid or the secretion of The yellow boxes indicate the formation of new or reabsorption by the thick ascending limb. The values in the boxes are approximations.

57 直血管的逆流被动交换和低血流使髓质高渗损失最小化 The vasa recta s countercurrent exchange and relatively low blood flow minimize washout of medullary hyperosmolality Y 逆流交换装臵 countercurrent exchanger, 降支直血管 升支直血管 皮质髓质 降支直血管 Figure 38-6 Model of countercurrent exchange. A, If blood simply flows from the cortex to the medulla through a straight tube, then the blood exiting the medulla will have a high osmolality (750 mosm), thus washing out the osmolality gradient of the medullary interstitium. The numbers in the yellow boxes indicate the osmolality (in mosm) inside the vasa recta, and the numbers in the green boxes indicate the osmolality of the interstitial fluid. B, If blood flows into and out of the medulla through a hairpin loop, then the water will leave the vessel, and solute will enter along the entire descending vessel and part of the ascending vessel. Along the rest of the ascending vessel, the fluxes of water and solute are reversed. The net effect is that the blood exiting the medulla is less hypertonic than that in A (450 versus 750 mosm), so that the kidney better preserves the osmotic gradient in the medulla. The values in the boxes are approximations. (Data from a model by Pitts RF: Physiology of the Kidney and Body Fluids. Chicago: Year Book, 1974.)

58 髓质收集管利用渗透压梯度产生浓缩尿 The MCD produces a concentrated urine by osmosis, driven by the osmotic gradient between the medullary interstitium and the lumen Z 直管交换器 MCD as straight-tube exchanger 间质液渗透压 皮质 外髓内髓 Figure 38-7 Opposing effects of NaCl and urea gradients on urine concentrating ability during antidiuresis. Numbers in the green boxes indicate the osmolalities (in mosm) of the interstitial fluid.

59 影响尿液浓缩和稀释的因素 Factors that modulate urinary concentration and dilution 1/ 髓质从皮髓边界至髓质乳突的渗透压梯度 : a/ 亨氏袢长度 : 袢长者 ( 如沙漠啮齿类 ) 比袢短者 ( 河狸 ) 浓缩力大 b/ 升支粗袢 NaCl 主动重吸收 : 增加腔面 Na + 运送至升支粗袢 ( 高 GFR 或高过滤分数 FF, 低近端小管 Na + 重吸收 ) 增强 NaCl 重吸收 ; 低 Na + 运送 ( 低 GFR, 增加的近端 Na + 和管业重吸收 ) 降低浓缩能力 Na-K 泵高活性加强 NaCl 重吸收, 同时抑制转运 ( 如亨氏袢利尿药 ) 降低浓缩力 c/ 高蛋白饮食 : 高蛋白饮食一定程度上促尿素产生及其在内髓间质积累, 增加尿浓缩力 2/ 髓质血流 : 低血流增加间质渗透压 高血流将溶质冲出髓质 3/ 收集管水通透性 : AVP 增加水通透性而增加水重吸收 4/ 亨氏袢和集合管腔液流 : 高流 ( 渗透性利尿 ) 降低逆流放大, 故降低髓质间质液渗透压 髓质收集管高流降低水 尿素在管平衡时 5/ 病理学变化 : 中枢尿崩症 diabetes insipidus (DI) 降低血浆 AVP; 肾源性尿崩症 DI 降低肾对 AVP. 反应

60 精氨酸血管加压素 Arginine vasopressin - AVP 下丘脑室旁 paraventricular 核和视上 supraoptic 核巨大神经元合成 AVP, 一个九肽, 又叫抗利尿激素 ADH 神经元将合成的 AVP 通过轴突囊泡转运, 运送至垂体后叶 posterior pituitary, 释放后 AVP 进入系统循环 远曲小管中 DCT 所剩余的水, 肾单元不同管段从初始集合管 ICT 开始进行不同程度的重吸收 这些管段中水的重吸收受到循环血中 AVP 的调控

61 AVP 增加肾单元远曲小管之后小管上皮细胞的水通透性 AVP increases water permeability in all nephron segments beyond the DCT 近端小管和降支细袢水通透性最高 因为这些小管上皮细胞顶端 基底段质膜 AQP1 蛋白高表达与近端小管和降支细袢相比, 升支细袢直至集合管固有性水通透性极低没有 AVP 刺激时初始集合管 ICT 和皮质收集管 CCT 水通透性低, 髓质收集管水通透性也较低 AVP 通过将 AQP2 蛋白转运至上皮细胞顶端质膜, 显著增加初始集合管 ICT 和皮质集合管 CCT, 以及外内髓集合管 OMCD IMCD 法人水通透性 水通道 AQP3 固有性表达于髓质集合管 MCD 旁侧面质膜 与 AQP1 类似,AQP3 的表达也不受 AVP 调节 AVP 刺激 AVP 敏感肾单元管段大量的水重吸收 但是当循环血中 AVP 浓度较低时, 如大量饮水后, 这些管段上皮细胞水通透性较低 故而流离远曲小管的管腔液在下游保持低渗 实际上没有 AVP 刺激时, 持续的 NaCl 重吸收导致管腔液越来越低渗, 产生大量稀释尿液

62 肾小管水分子通透性及 AVP 对其调节 Water permeability in different nephron segments and regulation by AVP 升支细袢髓质升支粗袢皮质升支粗袢远端曲小管连接管 AVP AVP AVP 皮质收集管外髓收集管内髓收集管 近端曲小管近端直小管降支细袢 Figure 38-8 Water permeability in different nephron segments. Note that the x-axis scale is logarithmic. (From Knepper MA, Rector FC: In Brenner BM [ed]: The Kidney, pp Philadelphia: WB Saunders, 1996.)

63 水通道在肾脏中的作用 Role of Aquaporins in Renal Water Transport 水通道 AQP1 介导近端小管和降支细袢大规模跨胞转运 但是水通道 AQP2, AQP3, 和 AQP4 主要在集合管主细胞表达, 介导集合管水向间质液的转运 小管上皮细胞顶端质膜 AQP2 是 AVP 调节的水通透性的分子基础 AQP3 和 AQP4 只在主细胞旁侧面质膜表达, 介导水分子从基底面向间质液的移动 长 短期水通透性调节都依赖于 AQP2 的存在 AVP camp PKA 系统调节水通道囊泡通过胞吐作用向顶端质膜转移 AQP2 密度增加后手通透性显著增加 长期调节过程中,AVP 基因转录增加, 增加主细胞 AQP2 蛋白含量

64 AVP 对收集管水分子通透性调节的分子机制 Cellular mechanism of AVP action in the collecting tubules and ducts 收 集 管 管 腔 面 AQP2 V 2 R 内髓收集管 AVP 收 Figure 38-9 Cellular mechanism of AVP action in the collecting tubules and ducts. 集 管 间 质 面 AQP3 AQP4

65 AVP 在外髓增加 NaCl 重吸收在内髓集合管增加尿素重吸收共同增加尿浓缩 AVP increases NaCl reabsorption in the outer medulla and urea reabsorption in the IMCD, enhancing urinary concentrating ability 外髓中 AVP 通过 camp 通路增加升支粗袢 TAL 对 NaCl 的重吸收 AVP 刺激细胞顶端质膜 Na/K/Cl 共转运和 K + 循环, 而增加外髓间质液渗透压, 和渗透压梯度以利于外髓收集管对水的重吸收 另外在 AVP 基因敲除动物 AVP 刺激升支粗袢细胞的生长 AVP 也通过 ENaC 刺激皮质收集管 Na + 重吸收 这些有关升支粗袢和皮质收集管的实验结果来自于啮齿类 在人升支粗袢和皮质收集管这些机制可能作用不大 内髓中 AVP 增强内髓集合管后 2/3 的尿素通透性 AVP-[cAMP] i 通路所触发的顶端质膜 AQP2 移膜作用, 同时也刺激细胞顶端质膜 UT-A1 和旁侧面质膜 UT-A3 的磷酸化, 增加其活性 结果尿素重吸收大幅增加, 间质液尿素浓度增加, 间接导致内髓渗透压梯度和驱动水的重吸收

66 水含量 ( 胞外渗透压 ) 的调节 Control of water content (extracellular osmolality) 1/ 两种机制控制水含量或身体总体渗透压 : 肾脏控制水的排泄, 干渴机制控制饮水 2/ 两种效应机制都是负反馈机制的一部分, 包括下丘脑中枢 3/ 渗透压增加刺激渗透压感受器, 反馈性刺激 AVP 的分泌减少肾脏水排泄 ; 触发干渴机制增加饮水 ) 两种相互补充的机制稳定渗透压及机体钠含量

67 血浆渗透压增加刺激下丘脑渗透压感受器, 引发 AVP 释放, 抑制水排泄 Increased plasma osmolality stimulates hypothalamic osmoreceptors that trigger the release of AVP, inhibiting water excretion 1/ Verney 实验室在 1940s 的动物实验发现在颈动脉注射高渗 NaCl 可突然中止已有水利尿. 2/ 摘除垂体后叶后颈动脉注射高渗 NaCl 不再有抗利尿 3/ 无论垂体后叶是否存在, 注射垂体后叶提取物皆可抑制利尿作用 Figure 40-6 Sensing of blood osmolality in the dog brain. i.a., intra-arterial (carotid) injection; i.v., intravenous injection; p.o., per os (by mouth). (Data from Verney EG: Proc R Soc Lond B 1947;135: )

68 血浆渗透压增加刺激下丘脑神经元释放 AVP Dependence of AVP release on plasma osmolality In healthy individuals, plasma osmolality is ~290 mosm. The threshold for AVP release is somewhat lower, ~280 mosm (red curve). Increasing the osmolality by only 1% higher than this level is sufficient to produce a detectable increase in plasma [AVP], which rises steeply with further increases in osmolality. Thus, hyperosmolality leads to increased levels of AVP, which completes the feedback loop by causing the kidneys to retain free water Figure 40-7 Dependence of AVP release on plasma osmolality. (Data from Robertson GL, Aycinena P, Zerbe RL: Am J Med 1982; 72: )

69 终板血管器 O V L T 穹隆下器官 S F O 渗透压受体对 AVP 合成和释放的控制 Control of AVP synthesis and release by osmoreceptors 视上核 室周器渗透压敏感神经元 下丘脑 室旁核 巨大神经元 孤束核投射神经元 垂体前页 垂体后叶 进入系统循环 Figure 40-8 Control of AVP synthesis and release by osmoreceptors. Osmoreceptors are located in the OVLT and the SFO, two areas that breech the blood-brain barrier. Signals from atrial, low-pressure baroreceptors travel with the vagus nerve to the nucleus tractus solitarii (NTS); a second neuron carries the signal to the hypothalamus.

70 渗透压增加刺激渗透压受体触发干渴反应 Increased osmolality stimulates a second group of osmoreceptors that trigger thirst, which promotes water intake 终板血管器穹隆下器官 渗透压敏感 N Figure 40-9 Feedback systems involved in the control of osmolality. PVN, paraventricular nucleus; SON, supraoptic nucleus of the hypothalamus.