Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan.
Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan.
Nephrol Dial Transplant. 2024 Mar 27;39(4):589-599. doi: 10.1093/ndt/gfad215.
Proteinuria is a well-established biomarker of chronic kidney disease (CKD) and a risk predictor of associated disease outcomes. Proteinuria is also a driver of CKD progression toward end-stage kidney disease. Toxic effects of filtered proteins on proximal tubular epithelial cells enhance tubular atrophy and interstitial fibrosis. The extent of protein toxicity and the underlying molecular mechanisms responsible for tubular injury during proteinuria remain unclear. Nevertheless, albumin elicits its toxic effects when degraded and reabsorbed by proximal tubular epithelial cells. Overall, healthy kidneys excrete over 1000 individual proteins, which may be potentially harmful to proximal tubular epithelial cells when filtered and/or reabsorbed in excess. Proteinuria can cause kidney damage, inflammation and fibrosis by increasing reactive oxygen species, autophagy dysfunction, lysosomal membrane permeabilization, endoplasmic reticulum stress and complement activation. Here we summarize toxic proteins reported in proteinuria and the current understanding of molecular mechanisms of toxicity of proteins on proximal tubular epithelial cells leading to CKD progression.
蛋白尿是慢性肾脏病 (CKD) 的一个既定生物标志物，也是相关疾病结局的风险预测因子。蛋白尿也是 CKD 向终末期肾病进展的驱动因素。滤过蛋白对近端肾小管上皮细胞的毒性作用增强了肾小管萎缩和间质纤维化。蛋白尿期间导致肾小管损伤的蛋白毒性的程度和潜在的分子机制尚不清楚。然而，当白蛋白被近端肾小管上皮细胞降解和重吸收时，它会产生毒性作用。总的来说，健康的肾脏会排泄超过 1000 种不同的蛋白质，当这些蛋白质被滤过和/或过量重吸收时，可能对近端肾小管上皮细胞造成潜在的伤害。蛋白尿可通过增加活性氧、自噬功能障碍、溶酶体膜通透性、内质网应激和补体激活来导致肾脏损伤、炎症和纤维化。在这里，我们总结了蛋白尿中报道的毒性蛋白，以及目前对导致 CKD 进展的蛋白质对近端肾小管上皮细胞毒性作用的分子机制的理解。
