Miyazaki Nagisa, Murata Ichijiro, Takemura Genzou, Okada Hideshi, Kanamori Hiromitsu, Matsumoto-Miyazaki Jun, Yoshida Gakuro, Izumi Kumiko, Kashi Hitomi, Niimi Kaori, Nishiwaki Ayuko, Miyazaki Tatsuhiko, Ohno Michiya, Ohashi Hiroshige, Suzuki Fumiaki, Minatoguchi Shinya
Second Department of Internal Medicine, Gifu University Graduate School of Medicine Gifu, Japan.
Second Department of Internal Medicine, Gifu University Graduate School of Medicine Gifu, Japan ; Department of Internal Medicine, Asahi University Mizuho, Gifu, Japan.
Int J Clin Exp Pathol. 2014 Oct 15;7(11):7485-96. eCollection 2014.
Prorenin receptor (PRR) has been implicated in the onset and progression of various renal diseases, though its possible association with immunoglobulin A (IgA) nephropathy remains unclear. In the present study, we tried to clarify expression and pathophysiological significance of PRR in IgA nephropathy. We immunohistochemically assessed PRR levels in renal biopsy specimens from 48 patients with IgA nephropathy and evaluated its relevance to the clinical and pathological features of the disease. PRR was detected mainly in renal tubular cells, which was confirmed at the subcellular level using immunoelectron microscopy. The PRR-positive area (%PRR area) correlated with daily urinary protein, which is known to reflect disease severity (r=0.286, P=0.049). PRR levels were weaker in tubular cells bordering areas of severe interstitial fibrosis, where α-smooth muscle actin-positive myofibroblasts were present. We also used immunohistochemical detection of microtubule-associated protein-1 light chain 3 (LC3) and electron microscopy to assess autophagy, a cytoprotective mechanism downstream of PRR. We noted an apparent coincidence between autophagy activation in tubular cells and PRR expression in the same cells. Taken together, our findings suggest that renal expression of PRR in IgA nephropathy may be a compensatory response slowing disease progression by preventing tubular cell death and subsequent fibrosis through activation of cytoprotective autophagic machinery. Further studies using different type of kidney diseases could draw conclusion if the present finding is a generalized observation beyond IgA nephropathy.
肾素原受体（PRR）已被证实与多种肾脏疾病的发生和发展有关，但其与免疫球蛋白A（IgA）肾病的潜在关联仍不明确。在本研究中，我们试图阐明PRR在IgA肾病中的表达及其病理生理意义。我们采用免疫组化方法评估了48例IgA肾病患者肾活检标本中PRR的水平，并评估了其与疾病临床和病理特征的相关性。PRR主要在肾小管细胞中检测到，免疫电子显微镜在亚细胞水平证实了这一点。PRR阳性面积（%PRR面积）与每日尿蛋白相关，已知尿蛋白可反映疾病严重程度（r=0.286，P=0.049）。在严重间质纤维化区域边界的肾小管细胞中，PRR水平较弱，这些区域存在α平滑肌肌动蛋白阳性的肌成纤维细胞。我们还采用免疫组化检测微管相关蛋白1轻链3（LC3）并结合电子显微镜评估自噬，自噬是PRR下游的一种细胞保护机制。我们注意到肾小管细胞中的自噬激活与同一细胞中的PRR表达明显一致。综上所述，我们的研究结果表明，IgA肾病中PRR的肾脏表达可能是一种代偿反应，通过激活细胞保护自噬机制来防止肾小管细胞死亡及随后的纤维化，从而减缓疾病进展。使用不同类型肾脏疾病进行的进一步研究可以得出结论，即目前的发现是否是IgA肾病之外的普遍观察结果。
