Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract.
Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract.
复制标题
生物力学力在肾脏和泌尿道先天性异常的超滤介导的肾小球损伤中的作用。
DOI：
10.1093/ndt/gfw430
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Sharma,Mukut
中科院分区：
文献类型：
--
作者：
Srivastava,Tarak;Thiagarajan,Ganesh;Alon,UriS;Sharma,Ram;El-Meanawy,Ashraf;McCarthy,EllenT;Savin,VirginiaJ;Sharma,Mukut
包括孤立肾在内的先天性肾尿路异常是儿童进行性慢性肾病（CKD）的主要病因。出生时患有CAKUT的儿童仅在青春期出现CKD的症状，并且对肾素-血管紧张素-醛固酮系统阻滞剂没有反应。成年早期CKD进展为终末期肾病的早期细胞改变尚不清楚。功能性肾单位丧失（包括孤立肾）引起的不适应超滤的机制尚不清楚。我们在生物力学力的背景下重新审视超滤现象，特别参考肾小球足细胞。毛细血管拉伸通过肾小球基底膜对足细胞施加拉伸应力。超滤液在细胞表面的流动直接对足细胞产生流体流动剪切应力（FFSS）。孤立肾动物模型足细胞表面的FFSS增加1.5- 2倍，其对足细胞的影响是一个正在进行的研究课题。足细胞(i)对拉伸和剪切力具有机械敏感性，（ii）使用前列腺素E2、血管紧张素ii或一氧化氮进行机械感知，（iii）使用特定的信号传导途径进行机械转导。我们讨论了(i)细胞对生物力学力反应的性质和差异，（ii）研究生物力学力的方法，以及（iii）生物力学力对足细胞和肾小球的影响。未来对FFSS的研究可能会确定早期干预策略的新目标，以补充和加强目前治疗CAKUT儿童的方案。
Congenital anomalies of the kidney and urinary tract (CAKUT) including solitary kidney constitute the main cause of progressive chronic kidney disease (CKD) in children. Children born with CAKUT develop signs of CKD only during adolescence and do not respond to renin-angiotensin-aldosterone system blockers. Early cellular changes underlying CKD progression to end-stage renal disease by early adulthood are not well understood. The mechanism of maladaptive hyperfiltration that occurs from loss of functional nephrons, including solitary kidney, is not clear. We re-examine the phenomenon of hyperfiltration in the context of biomechanical forces with special reference to glomerular podocytes. Capillary stretch exerts tensile stress on podocytes through the glomerular basement membrane. The flow of ultrafiltrate over the cell surface directly causes fluid flow shear stress (FFSS) on podocytes. FFSS on the podocyte surface increases 1.5- to 2-fold in animal models of solitary kidney and its effect on podocytes is a subject of ongoing research. Podocytes (i) are mechanosensitive to tensile and shear forces, (ii) use prostaglandin E2, angiotensin-II or nitric oxide for mechanoperception and (iii) use specific signaling pathways for mechanotransduction. We discuss (i) the nature of and differences in cellular responses to biomechanical forces, (ii) methods to study biomechanical forces and (iii) effects of biomechanical forces on podocytes and glomeruli. Future studies on FFSS will likely identify novel targets for strategies for early intervention to complement and strengthen the current regimen for treating children with CAKUT.