Primary focal segmental glomerulosclerosis (FSGS)

Primary or idiopathic focal segmental glomerulosclerosis (FSGS) a cause of nephrotic syndrome in children and adolescents, as well as an important cause of end stage renal disease in adults. FSGS is mainly associated with foot process effacement, proliferation of mesangial, endothelial and epithelial cells in the early stages followed by collapse of glomerular capillaries leading to scarring. It may lead to dramatic manifestations such as proteinuria, hypoaluminemia, and hypertension. Also, there are many inheritable genetic abnormalities that can cause podocyte damage of FSGS caused by mutations in proteins that are important for podocyte function. The genes include CD2AP, MYO1E, WNT1, and LAMB2. On the far left, the diagram illustrates molecular interactions between a normal podocyte and matrix interactions. ACTN4 and SYNPO and DAG1 interacting with AGRN associate with the actin cytoskeleton; these actin associated proteins might play a role in maintaining podocyte and GBM architecture. DAG1 binds to UTRN, which in turn binds an actin filament, thus completing the link between the actin-based cytoskeleton and the extracellular matrix. Podocyte foot processes are anchored to the glomerular basement membrane (GBM) via ITGB1 and ITGA3 integrin complex and DAG1-UTRN complex. Transmembrane proteins such as LAMA5 and CD151 bind to ITGB1 and ITGA3, respectively. The intracellular integrins combine with cytoskeletal via intermediates which include TLN1, VCL, and PAX complex and the ILK, PARVA, and LIMS1 complex. (Guanghua Hu et. al 2013 - Biomedicine and Aging Pathology vol 3) Upon primary podocyte injury, there are multiple pathways involved in podocyte injury. "Sustaining NPHS1 and phosphorylation might contribute to both anti-apoptotic signaling and actin polymerization. The CD80 pathway may be targeted by TLR4 or blocking the binding of B7-1 to slit diaphragm structure proteins such as KIRREL2/3. PLAUR could be inhibited by interfering with binding of PLAUR and ITGAV/B3 integrin, inhibiting ITGB3 integrin activation, or inhibiting binding of ITGAV/B3 integrin to VTN. The notch pathway can be targeted by interfering with its upstream activation by blocking the TGF-β1 effect, inhibiting γ-secretase, which is required for proteolytic receptor activation, or interfering with target gene transcription." (Reiser J. et al 2010 - Kidney Int vol 77) Post podocyte development, increased activation of NOTCH1 and WNT/CTNNB1 activities contribute to glomerulosclerosis. Expression of JAG1 on the ligand-expressing cell induces proteolytic cleavage of the Notch receptor on the signal-receiving cell, releasing the NOTCH1. DKK1 inhibits WNT1 binding to LRP5/6. By inhibiting the destruction of CTNNB1, CTNNB1 is stablilized. "The CTSL pathway could be targeted by specifically inhibiting CTSL expression or activity, shifting the equilibrium of SYNPO toward the phosphorylated form by inhibiting calcineurin-mediated dephosphorylation or enhancing PKA or CAMK2B-mediated phosphorylation, protecting SYNPO and DNM1 by compounds that bind to the CTSL cleavage site, or delivering cleavage-resistant SYNPO and DNM1 mutants." (Reiser J. et al 2010 - Kidney Int vol 77) The destruction of podocyte's cytoskeleton architecture leads to lose of normal podocyte epitopes such as VIM, SYNPO, and WT1, and lose of cyclin-dependent kinase inhibitors CDKN1C and CDKN1B. Also, podocytes acquire proliferation of CDKN1A. This leads to podocytopenia which have been shown to cause primary FSGS and then followed by end-stage renal disease (ESRD). FSGS is also induced by microRNA-193a and its downregulation of WT1, destroying podocyte foot processes. There is insufficient evidence that segmental glomerular lesions can be caused by other drugs or toxins, apart from some used experimentally such as doxorubicin and puromycin aminonucleoside. Treatments such as steroids, high-dose cyclosporine, ritxuximab can reduce proteinuria based on their immunosuppressive properties and through stabilization of the podocyte actin cytoskeleton.

原发性或特发性局灶节段性肾小球硬化症（FSGS），是儿童和青少年肾病综合征的病因之一，也是成人终末期肾病的重要原因。FSGS主要与足突吸收、早期系膜细胞、内皮细胞和上皮细胞的增生有关，随后为肾小球毛细血管塌陷导致瘢痕形成。它可能导致剧烈的临床表现，如蛋白尿、低白蛋白血症和高血压。此外，还存在许多可遗传的遗传异常，这些异常可由对足细胞功能至关重要的蛋白质突变引起，导致FSGS的足细胞损伤。相关基因包括CD2AP、MYO1E、WNT1和LAMB2。在最左侧的图中，展示了正常足细胞与基质之间的分子相互作用。ACTN4、SYNPO和DAG1与AGRN相互作用，与肌动蛋白细胞骨架相关；这些与肌动蛋白相关的蛋白可能在维持足细胞和肾小球基底膜（GBM）结构中发挥作用。DAG1与UTRN结合，进而结合肌动蛋白微丝，从而完成基于肌动蛋白的细胞骨架与细胞外基质之间的连接。足细胞足突通过ITGB1和ITGA3整合素复合物以及DAG1-UTRN复合物锚定在肾小球基底膜（GBM）上。跨膜蛋白如LAMA5和CD151分别与ITGB1和ITGA3结合。细胞内整合素通过TLN1、VCL和PAX复合物以及ILK、PARVA和LIMS1复合物等中介与细胞骨架结合。（胡广华等，2013 - 生物医学与衰老病理学杂志第3卷）在原发性足细胞损伤后，存在多种参与足细胞损伤的途径。'维持NPHS1和磷酸化可能有助于抗凋亡信号和肌动蛋白聚合。CD80途径可能通过TLR4靶向，或通过阻断B7-1与裂隙隔膜结构蛋白（如KIRREL2/3）的结合来靶向。通过干扰PLAUR与ITGAV/B3整合素结合、抑制ITGB3整合素激活或抑制ITGAV/B3整合素与VTN结合，可以抑制PLAUR。通过干扰其上游激活、抑制γ-分泌酶（这是蛋白酶受体活化的必需因子）或干扰靶基因转录，可以靶向 notch 途径。'（Reiser J. 等，2010 - 肾脏国际杂志第77卷）足细胞发育后，NOTCH1和WNT/CTNNB1活性的增加有助于肾小球硬化。在配体表达细胞上表达JAG1诱导信号接收细胞上Notch受体的蛋白水解裂解，释放NOTCH1。DKK1抑制WNT1与LRP5/6的结合。通过抑制CTNNB1的破坏，CTNNB1得以稳定。'通过特异性抑制CTSL表达或活性、通过抑制钙调神经磷酸酶介导的去磷酸化或增强PKA或CAMK2B介导的磷酸化、通过与CTSL切割位点结合的化合物保护SYNPO和DNM1、或递送切割抵抗的SYNPO和DNM1突变体，可以靶向CTSL途径。'（Reiser J. 等，2010 - 肾脏国际杂志第77卷）足细胞细胞骨架结构的破坏导致正常足细胞表位（如VIM、SYNPO和WT1）以及细胞周期依赖性激酶抑制因子CDKN1C和CDKN1B的丢失。此外，足细胞获得CDKN1A的增殖。这导致足细胞减少，据研究表明，这是原发性FSGS的病因，随后继发终末期肾病（ESRD）。FSGS还由microRNA-193a及其对WT1的下调诱导，破坏足细胞足突。除了一些实验中使用的药物或毒素（如多柔比星和嘌呤霉素核苷酸）外，缺乏足够的证据表明节段性肾小球病变可由其他药物或毒素引起。基于其免疫抑制特性和通过稳定足细胞肌动蛋白细胞骨架，糖皮质激素、高剂量环孢素和利妥昔单抗等治疗可减少蛋白尿。