Teng Jiamin, Russell William J, Gu Xin, Cardelli James, Jones M Lamar, Herrera Guillermo A
Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Lab Invest. 2004 Apr;84(4):440-51. doi: 10.1038/labinvest.3700069.
Patients with plasma cell dyscrasias may have circulating light chains (LCs), some of which are nephrotoxic. Nephrotoxic LCs can affect the various renal compartments. Some of these LCs may produce predominantly proximal tubular damage, while others are associated with distal nephron obstruction (the so-called "myeloma kidney"). Both these are considered tubulopathic (T) LCs. A receptor has been found in proximal tubular cells (cubilin/megalin complex), which mediates the absorption of LCs and is involved in the pathogenesis of tubulopathies that occurs in these patients. Another group of nephrotoxic LCs is associated with glomerular damage and these are considered as glomerulopathic (G). These patients with G-LCs may develop AL-amyloidosis (AL-Am) or LC deposition disease (LCDD). Recent evidence indicates that the physicochemical characteristics (amino-acid composition and conformation of the variable region) of a given nephrotoxic LC may be the most significant factor in determining the type and location of renal damage within the nephron. Other factors may also be involved, including yet uncharacterized host factors that may include genetic polymorphism, among others. Interestingly, the amount of LC production by the clone of plasma cells does not correlate directly with the severity of the renal alterations. Understanding the nature of the interactions between G-LCs and mesangial cells (MCs) is crucial to define key steps that may be targeted for therapeutic purposes. Experimental studies have delineated important aspects pertaining to interactions between G-LCs and MCs, indicating that these interactions are receptor mediated. The data presented in the current study support a single receptor present on MCs for both LCDD and AL-LCs, as clearly demonstrated with competition and colocalization immunofluorescence (IF) studies. This receptor resides in caveolae present on the plasma membrane of HMCs and is overexpressed when HMCs are incubated with G-LCs but not TLCs. Caveolae play a fundamental role in receptor-mediated endocytosis, a crucial process in the internalization of AL-LCs and amyloidogenesis. LC internalization is clathrin mediated. The data also indicate that intracellular trafficking in MCs is different for AL-LCs and LCDD-LCs. AL-LCs are delivered to the mature lysosomal compartment where amyloid formation occurs. LCDD-LCs alter mesangial function and phenotype by interacting with the MC surface membranes through similar receptors as the AL-LCs. The data also demonstrated that cubilin and megalin were absent on MCs, so the receptor involved is different from the one already characterized in the proximal tubules.
浆细胞异常增生症患者可能存在循环轻链（LCs），其中一些具有肾毒性。肾毒性轻链可影响肾脏的各个部分。这些轻链中的一些可能主要导致近端肾小管损伤，而另一些则与远端肾单位梗阻有关（即所谓的“骨髓瘤肾病”）。这两种情况均被认为是肾小管病变（T）轻链。已在近端肾小管细胞中发现一种受体（cubilin/megalin复合物），它介导轻链的吸收，并参与这些患者发生的肾小管病变的发病机制。另一组肾毒性轻链与肾小球损伤有关，这些被视为肾小球病变（G）轻链。这些G轻链患者可能会发展为AL淀粉样变性（AL-Am）或轻链沉积病（LCDD）。最近的证据表明，特定肾毒性轻链的物理化学特性（可变区的氨基酸组成和构象）可能是决定肾单位内肾损伤类型和位置的最重要因素。其他因素可能也参与其中，包括尚未明确的宿主因素，其中可能包括基因多态性等。有趣的是，浆细胞克隆产生的轻链量与肾脏改变的严重程度并无直接关联。了解G轻链与系膜细胞（MCs）之间相互作用的本质对于确定可能作为治疗靶点的关键步骤至关重要。实验研究已经阐明了与G轻链和系膜细胞之间相互作用有关的重要方面，表明这些相互作用是受体介导的。本研究中呈现的数据支持系膜细胞上存在一种同时介导LCDD和AL轻链的单一受体，竞争和共定位免疫荧光（IF）研究清楚地证明了这一点。该受体存在于人类系膜细胞（HMCs）质膜上的小窝中，当HMCs与G轻链而非T轻链孵育时会过度表达。小窝在受体介导的内吞作用中起重要作用，这是AL轻链内化和淀粉样蛋白形成的关键过程。轻链内化是网格蛋白介导的。数据还表明，系膜细胞内AL轻链和LCDD轻链的运输途径不同。AL轻链被转运至成熟的溶酶体区室，在那里发生淀粉样蛋白形成。LCDD轻链通过与AL轻链相同的受体与系膜细胞表面膜相互作用，从而改变系膜细胞功能和表型。数据还表明，系膜细胞上不存在cubilin和megalin，因此所涉及的受体与近端肾小管中已确定的受体不同。
