Department of Pharmaceutics, University of Washington, Seattle, Washington.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.
J Am Soc Nephrol. 2022 May;33(5):949-965. doi: 10.1681/ASN.2021060751. Epub 2022 Feb 23.
The kidneys efficiently filter waste products while retaining serum proteins in the circulation. However, numerous diseases compromise this barrier function, resulting in spillage of serum proteins into the urine (proteinuria). Some studies of glomerular filtration suggest that tubules may be physiologically exposed to nephrotic-range protein levels. Therefore, whether serum components can directly injure the downstream tubular portions of the kidney, which in turn can lead to inflammation and fibrosis, remains controversial.
We tested the effects of serum protein exposure in human kidney tubule microphysiologic systems and with orthogonal epigenomic approaches since animal models cannot directly assess the effect of serum components on tubules.
Serum, but not its major protein component albumin, induced tubular injury and secretion of proinflammatory cytokines. Epigenomic comparison of serum-injured tubules and intact kidney tissue revealed canonical stress-inducible regulation of injury-induced genes. Concordant transcriptional changes in microdissected tubulointerstitium were also observed in an independent cohort of patients with proteinuric kidney disease.
Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention.
肾脏能有效地过滤废物，同时保留循环中的血清蛋白。然而，许多疾病会损害这种屏障功能，导致血清蛋白渗漏到尿液中（蛋白尿）。一些肾小球滤过的研究表明，小管可能在生理上暴露于肾病范围的蛋白水平。因此，血清成分是否能直接损伤肾脏下游的管状部分，进而导致炎症和纤维化，这仍然存在争议。
我们在人肾小管微生理系统中测试了血清蛋白暴露的影响，并采用正交表观基因组学方法，因为动物模型不能直接评估血清成分对小管的影响。
血清，而不是其主要蛋白成分白蛋白，诱导管状损伤和促炎细胞因子的分泌。血清损伤的小管和完整肾脏组织的表观基因组比较显示，损伤诱导基因的典型应激诱导调节。在另一组蛋白尿性肾病患者的独立队列中，也观察到微切割的肾小管间质中一致的转录变化。
我们的结果表明血清蛋白在管状损伤中起因果作用，并确定了用于干预的调节机制和新途径。
