Haddad George, Blaine Judith
Division of Renal Disease and Hypertension, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 E 19th Ave, Aurora, CO 80045, USA.
Cells. 2025 Mar 1;14(5):364. doi: 10.3390/cells14050364.
Nephrin is an essential constituent of the slit diaphragm of the kidney filtering unit. Loss of nephrin expression leads to protein leakage into the urine, one of the hallmarks of kidney damage. Autoantibodies against nephrin have been reported in patients with minimal change disease and recurrent focal segmental glomerulosclerosis. Understanding the mechanism of nephrin loss may help improve or lead to the development of novel treatment strategies. In this study, we demonstrated the important function of miR-204-5p expression on the protection of nephrin from anti-nephrin antibodies present in nephrotoxic serum (NTS). In addition, we identified that aspartyl protease cathepsin D is one enzyme that may be involved in nephrin enzymatic degradation and that cathepsin D is a direct target of miR-204-5p gene regulation. The regulation of miR-204-5p expression was determined to be regulated by the long noncoding RNA Josd1-ps. In an NTS in vivo animal model, treatment with the pan aspartic protease inhibitor Pepstatin A ameliorated renal damage. Finally, we showed that the expression of miR-204-5p had a nephrin-protecting function in vitro. Developing a method of delivery of miR-204-5p specifically to podocytes in vivo may provide a novel method of nephroprotection against nephrin autoantibodies.
Nephrin是肾脏滤过单位裂孔隔膜的重要组成部分。Nephrin表达缺失会导致蛋白质漏入尿液，这是肾损伤的标志性特征之一。在微小病变病和复发性局灶节段性肾小球硬化症患者中已报道存在抗Nephrin自身抗体。了解Nephrin缺失的机制可能有助于改进或开发新的治疗策略。在本研究中，我们证明了miR-204-5p表达在保护Nephrin免受肾毒性血清（NTS）中存在的抗Nephrin抗体影响方面的重要功能。此外，我们确定天冬氨酸蛋白酶组织蛋白酶D是一种可能参与Nephrin酶促降解的酶，并且组织蛋白酶D是miR-204-5p基因调控的直接靶点。已确定miR-204-5p表达受长链非编码RNA Josd1-ps调控。在NTS体内动物模型中，用泛天冬氨酸蛋白酶抑制剂胃蛋白酶抑素A治疗可改善肾损伤。最后，我们表明miR-204-5p的表达在体外具有保护Nephrin的功能。开发一种在体内将miR-204-5p特异性递送至足细胞的方法可能提供一种针对Nephrin自身抗体的新型肾保护方法。
