Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, United States.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, United States.
Elife. 2024 Aug 29;12:RP91260. doi: 10.7554/eLife.91260.
HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes, and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN.
HIV 疾病在美国仍然普遍存在，慢性肾脏病仍然是 HIV-1 阳性患者发病的主要原因。宿主双链 RNA（dsRNA）激活的蛋白激酶（PKR）是病毒 dsRNA 的传感器，包括 HIV-1。我们表明，化合物 C16 抑制 PKR 可改善 Tg26 转基因小鼠模型中的 HIV 相关性肾病（HIVAN）肾脏表型，并逆转线粒体功能障碍。单细胞 RNA-seq 和批量 RNA-seq 数据的综合分析表明，氧化磷酸化是下调最明显的途径之一，并确定信号转导和转录激活因子 3（STAT3）为潜在的介导因子。我们在 Tg26 小鼠中鉴定出一种新型富含线粒体转录物的近端肾小管细胞簇。足细胞表现出高水平的 HIV-1 基因表达和细胞骨架相关基因的失调，并且这些细胞去分化。在受损的近端肾小管中，细胞间相互作用分析表明，促纤维化 PKR-STAT3-血小板衍生生长因子（PDGF）-D 途径被激活。这些发现表明，PKR 抑制和线粒体挽救可能是 HIVAN 的潜在新治疗方法。
