Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells. To study the consequences of PDGFR-β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR-β activation resembled those found in patients. In conclusion, PDGFR-β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.

中文翻译：

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失调的间充质 PDGFR-β 会导致肾脏纤维化。

肾纤维化的特征是血小板源性生长因子受体-β (PDGFR-β) 阳性间充质细胞的扩张和激活。为了研究 PDGFR-β 激活的后果，我们使用转基因小鼠开发了原发性肾纤维化模型，PDGFR-β 特别在肾间充质细胞中激活，驱动其病理性增殖和表型向肌成纤维细胞的转变。这导致进行性系膜增生性肾小球肾炎、系膜硬化和间质纤维化，并由于成纤维细胞产生促红细胞生成素的丧失而伴有进行性贫血。纤维化后期引起继发性肾小管上皮损伤，同时发生微炎症，并加剧高血压和梗阻性肾病的进展。与肾小球相比，抑制 PDGFR 激活可以更有效地逆转肾小管间质的纤维化。PDGFR-β 激活的小鼠中的基因表达特征与患者中发现的基因表达特征相似。总之，仅 PDGFR-β 激活就足以诱导进行性肾纤维化和衰竭，类似于人类慢性肾病的关键方面。我们的数据提供了直接证据，证明纤维化本身可以导致慢性器官损伤，并建立原发性纤维化模型，允许针对纤维化进展和消退的具体研究。