Del Prete Dorella, Gambaro Giovanni, Lupo Antonio, Anglani Franca, Brezzi Brigida, Magistroni Riccardo, Graziotto Romina, Furci Luciana, Modena Francesca, Bernich Patrizia, Albertazzi Alberto, D'Angelo Angela, Maschio Giuseppe
Division of Nephrology, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy.
Kidney Int. 2003 Jul;64(1):149-59. doi: 10.1046/j.1523-1755.2003.00065.x.
The renin-angiotensin system (RAS) seems to play a pivotal role in progression of immunoglobulin A (IgA) nephropathy (IgAN). Accordingly, in patients with IgAN a relationship between the RAS and the fibrogenic cascade triggered by transforming growth factor-beta1 (TGF-beta1) should be observed. This study was carried out to obtain deeper insight into the regulation of RAS and the interaction with TGF-beta1 in the diseased kidney.
Twenty renal biopsies from IgAN patients and five from renal cancer patients (controls) were analyzed in both microdissected glomerular and tubulointerstitial compartments by reverse transcription-polymerase chain reaction (RT-PCR). All patients had normal renal function. The expression of the following genes was determined: angiotensinogen (Agtg), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 and type II (AT1 and AT2 receptors), TGF-beta1, collagen IV (Coll IV), alpha-smooth muscle actin (alpha-SMA). Quantitative data were confirmed for TGF-beta1 and ACE genes by real-time PCR. Results. RAS genes were overexpressed in IgAN patients vs. control subjects. There was no difference between glomerular and tubulointerstitial RAS gene expression levels. On the contrary, the overactivation of fibrogenic cascade genes (TGF-beta1, Coll IV, alpha-SMA) in the tubulointerstitium was observed (TGF-beta1, glomerular 0.14 +/- 0.10 SD; tubulointerstial 0.34 +/- 0.20; P = 0.000) (alpha-SMA, glomerular 0.08 +/- 0.07; tubulointerstitial 0.35 +/- 0.19; P = 0.000) (Coll IV, glomerular 0.12 +/- 0.11; tubulointerstitial 0.22 +/- 0.10; P = 0.03). This fibrogenic cascade seems to be triggered by RAS as indicated by statistically significant correlations between the expression of their respective genes. A direct relationship between the putative Ang II activity and the expression of AT receptor genes was found in the tubulointerstitium, whereas in the glomeruli this relationship was negative. In the interstitium, statistically significant positive relationships emerged between interstitial infiltrates and the gene expression of Agtg, AT1 receptor, Coll IV, and TGF-beta1.
This study demonstrates that a tight regulation of the intrarenal RAS exists in IgAN and that it follows the general rules disclosed in animal models. Moreover, the RAS seems to be activated early in the diseased kidney and it appears that such activation drives inflammation and a parallel stimulation of the TGF-beta fibrogenic loop, particularly at the tubulointerstitial level.
肾素 - 血管紧张素系统（RAS）似乎在免疫球蛋白A（IgA）肾病（IgAN）进展中起关键作用。因此，在IgAN患者中，应观察到RAS与由转化生长因子 - β1（TGF - β1）触发的纤维化级联反应之间的关系。本研究旨在更深入地了解患病肾脏中RAS的调节及其与TGF - β1的相互作用。
通过逆转录 - 聚合酶链反应（RT - PCR）对20例IgAN患者的肾活检组织和5例肾癌患者（对照组）的肾活检组织进行显微切割肾小球和肾小管间质区分析。所有患者肾功能正常。测定以下基因的表达：血管紧张素原（Agtg）、肾素、血管紧张素转换酶（ACE）、血管紧张素II（Ang II）1型和2型（AT1和AT2受体）、TGF - β1、IV型胶原（Coll IV）、α - 平滑肌肌动蛋白（α - SMA）。通过实时PCR对TGF - β1和ACE基因的定量数据进行确认。结果：与对照组相比，IgAN患者的RAS基因过度表达。肾小球和肾小管间质RAS基因表达水平无差异。相反，观察到肾小管间质中纤维化级联基因（TGF - β1、Coll IV、α - SMA）的过度激活（TGF - β1，肾小球0.14±0.10标准差；肾小管间质0.34±0.20；P = 0.000）（α - SMA，肾小球0.08±0.07；肾小管间质0.35±0.19；P = 0.000）（Coll IV，肾小球0.12±0.11；肾小管间质0.22±0.10；P = 0.03）。这种纤维化级联反应似乎由RAS触发，其各自基因的表达之间存在统计学显著相关性表明了这一点。在肾小管间质中发现假定的Ang II活性与AT受体基因表达之间存在直接关系，而在肾小球中这种关系为负。在间质中，间质浸润与Agtg、AT1受体、Coll IV和TGF - β1的基因表达之间出现统计学显著的正相关。
本研究表明IgAN中存在肾内RAS的严格调节，且遵循动物模型中揭示的一般规律。此外，RAS似乎在患病肾脏中早期被激活，并且这种激活似乎驱动炎症以及TGF - β纤维化环的平行刺激，特别是在肾小管间质水平。
