Large increases in glomerular protein filtration induce major changes in body homeostasis and are associated with a higher risk of kidney functional decline and cardiovascular disease. We investigated how elevated protein exposure modifies the landscape of tubular function along the entire nephron, to understand the cellular changes that mediate these important clinical phenomena. Methods We conducted single-nucleus RNA sequencing, functional intravital imaging, and antibody staining to spatially map transport processes along the mouse kidney tubule. We then delineated how these were altered in a transgenic mouse model of inducible glomerular proteinuria (POD-ATTAC) at 7 and 28 days. Results Glomerular proteinuria activated large-scale and pleiotropic changes in gene expression in all major nephron sections. Extension of protein uptake from early (S1) to later (S2) parts of the proximal tubule initially triggered dramatic expansion of a hybrid S1/2 population, followed by injury and failed repair, with the cumulative effect of loss of canonical S2 functions. Proteinuria also induced acute injury in S3. Meanwhile, overflow of luminal proteins to the distal tubule caused transcriptional convergence between specialized regions and generalized dedifferentiation. Conclusions Proteinuria modulated cell signaling in tubular epithelia and caused distinct patterns of remodeling and injury in a segment-specific manner. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_05_01_ASN0000000000000357.mp3...

中文翻译：

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肾小管对肾小球蛋白尿反应的时空景观


肾小球蛋白滤过的大量增加会引起身体稳态的重大变化，并与肾功能下降和心血管疾病的风险增加有关。我们研究了蛋白质暴露量升高如何改变整个肾单位的肾小管功能景观，以了解介导这些重要临床现象的细胞变化。方法 我们进行了单核 RNA 测序、功能性活体成像和抗体染色，以在空间上绘制沿小鼠肾小管的运输过程。然后，我们描述了这些在诱导型肾小球蛋白尿 （POD-ATTAC） 的转基因小鼠模型中在 7 天和 28 天时是如何改变的。结果 肾小球蛋白尿激活了所有主要肾单位切片基因表达的大规模和多效性变化。蛋白质摄取从近端小管的早期 （S1） 部分延伸到晚期 （S2） 部分最初引发了杂交 S1/2 群体的急剧扩张，随后是损伤和修复失败，具有典型 S2 功能丧失的累积效应。蛋白尿也诱导了 S3 的急性损伤。同时，管腔蛋白溢出到远端小管导致特化区域之间的转录收敛和广义去分化。结论 蛋白尿调节肾小管上皮细胞信号传导，并以节段特异性方式引起不同的重塑和损伤模式。播客 本文包含 https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_05_01_ASN0000000000000357.mp3...