Abbate M, Zoja C, Rottoli D, Corna D, Perico N, Bertani T, Remuzzi G
Mario Negri Institute for Pharmacological Research, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Italy.
J Am Soc Nephrol. 1999 Apr;10(4):804-13. doi: 10.1681/ASN.V104804.
In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: (1) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; (2) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that (1) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; (2) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis.
在蛋白尿性肾小球病中，过量蛋白质进入肾小管是导致间质炎症和免疫反应进而引起进行性损伤的潜在触发因素，也是抗蛋白尿药物肾脏保护作用的关键靶点。在转运至近端小管的蛋白质中，补体第三成分（C3）可在局部被激活，并在蛋白质重吸收部位促进炎症反应。我们对肾大部切除（RMR，5/6肾切除）大鼠进行了实验，目的如下：（1）通过双重免疫荧光分析研究术后不同时间点近端小管中Ig（IgG）和补体沉积、间质巨噬细胞浸润及MHC II类表达情况；（2）评估赖诺普利（血管紧张素转换酶抑制剂[ACEi]，术后第1天或第7天起饮水中含25 mg/L）是否能在第30天时限制IgG和C3的蓄积及间质炎症。在术后7天的残余肾脏中，在近端小管的局灶区域可检测到IgG和C3的细胞内染色；C3局限于IgG阳性的肾小管细胞，且无间质ED-1巨噬细胞和MHC II阳性细胞浸润。在术后14天和30天的残余肾脏中，近端小管IgG和C3染色与间质浸润的出现相关，这些浸润优先定位于两种蛋白质均为阳性的小管区域。给予ACEi的RMR大鼠在第30天时尿蛋白排泄水平、肾小管IgG和C3反应性及肾脏间质细胞浸润无增加或增加有限，即使ACEi从术后第7天开始使用。这些发现表明：（1）在RMR中，近端小管细胞中IgG和C3蓄积后，相邻间质会出现白细胞浸润和MHC II过表达；（2）ACEi在预防蛋白尿的同时，可限制IgG和C3在肾小管的蓄积以及间质炎症。数据表明，ACE抑制可通过限制近端小管早期异常蛋白质转运以及过量蛋白质重吸收的后续有害影响来发挥肾脏保护作用，这些有害影响包括补体的蓄积和局部激活以及已知可促进间质炎症和纤维化的趋化因子和内皮素基因的诱导。
