Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development
Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development
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DOI：
10.1016/j.kint.2022.12.012
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发表时间：
2023-02-21
影响因子：
19.6
通讯作者：
Lee, Kyung
中科院分区：
文献类型：
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作者：
Chen, Yuqiang;Chen, Ya;Lee, Kyung
慢性肾脏病（CKD）是人类免疫缺陷病毒（HIV）阳性个体发病的常见原因。HIV感染导致广泛的肾细胞损伤，包括肾小管上皮细胞（TEC）损伤。在HIV-1蛋白中，病毒蛋白R（Vpr）的病理作用已得到充分证实，包括DNA损伤反应、细胞周期阻滞和细胞死亡。几项体外研究已经揭示了驱动Vpr在肾小管上皮细胞中致细胞病变作用的分子途径。然而，Vpr对肾小管损伤和CKD发病机制的体内影响尚未得到彻底研究。在这里，我们使用一种新的诱导型肾小管上皮细胞特异性Vpr转基因小鼠模型，以表明Vpr表达导致进行性肾小管间质损伤，间质炎症和纤维化，以及肾小管囊肿的发展。重要的是，表达Vpr的肾小管上皮细胞表现出显着的肥大、异常细胞分裂和萎缩;所有这些都让人想起在人类艾滋病毒相关肾病（HIVAN）中观察到的肾小管损伤。单细胞RNA测序分析揭示了特定肾小管亚群中Vpr介导的转录组学反应，并强调了p53在表达Vpr的肾小管上皮细胞中调节细胞代谢、增殖和死亡途径的潜在多方面作用。因此，我们的研究表明，HIV Vpr在肾小管细胞中的表达足以诱导HIV样肾小管间质损伤和纤维化，独立于肾小球硬化和蛋白尿。此外，由于这种新的小鼠模型发展为弥漫性纤维化和肾衰竭的进行性CKD，因此它可以作为检查体内肾脏疾病进展和纤维化机制的有用工具。
Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.