Sudhindar Praveen Dhondurao, Olinger Eric, Sentell Zachary T, Mabillard Holly, Dicka Barbora, Wood Katrina, Rutland Dominic, Collins Catherine, Trevisan-Herraz Marco, Sayer John A, Arcila-Galvis Juliana E
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
J Cell Sci. 2025 Oct 15;138(20). doi: 10.1242/jcs.264141. Epub 2025 Sep 8.
Nephronophthisis (NPHP) is a recessive tubulointerstitial nephropathy and a leading genetic cause of kidney failure in children and young adults. The most common genetic cause is a homozygous deletion of NPHP1, which encodes nephrocystin-1, a protein essential for primary cilium structure and cell junctions. Using personalized medicine and deep phenotyping, we investigated a family with three siblings carrying a homozygous NPHP1 deletion. We compared kidney biopsy tissue and human urine-derived renal epithelial cells (hURECs) from these individuals. Bulk RNA-seq on patient hURECs revealed altered expression in EGFR signalling, extracellular components and adherens junctions, which is consistent with the known roles for nephrocystin-1. Treatment with alprostadil, a proposed NPHP therapy, increased ciliation but worsened ciliary elongation. By contrast, the EGFR kinase inhibitor AG556 rescued of ciliary length and morphology. Transcriptional profiling post-treatment showed AG556 reversed the disease signature more effectively that alprostadil. These findings suggest that EGFR inhibition might offer a more promising therapeutic strategy for NPHP1-associated renal ciliopathy, warranting further testing in in vivo models before clinical application.
肾单位肾痨（NPHP）是一种隐性肾小管间质性肾病，是儿童和青年肾衰竭的主要遗传病因。最常见的遗传病因是NPHP1的纯合缺失，NPHP1编码肾囊肿蛋白-1，这是一种对初级纤毛结构和细胞连接至关重要的蛋白质。利用个性化医疗和深度表型分析，我们研究了一个有三个携带NPHP1纯合缺失的兄弟姐妹的家庭。我们比较了这些个体的肾活检组织和人尿源性肾上皮细胞（hURECs）。对患者hURECs进行的大量RNA测序显示，表皮生长因子受体（EGFR）信号传导、细胞外成分和黏着连接中的表达发生了改变，这与肾囊肿蛋白-1的已知作用一致。用一种提议的NPHP治疗药物前列地尔治疗，增加了纤毛形成，但使纤毛伸长恶化。相比之下，EGFR激酶抑制剂AG556挽救了纤毛长度和形态。治疗后的转录谱分析表明，AG556比前列地尔更有效地逆转了疾病特征。这些发现表明，抑制EGFR可能为NPHP1相关的肾纤毛病提供一种更有前景的治疗策略，在临床应用前需要在体内模型中进行进一步测试。
