Treatment with 2,4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific Coq6 Knockout Mice

作者：Eugen Widmeier, Merlin Airik, Hannah Hugo, David Schapiro, Johannes Wedel, Chandra C. Ghosh, Makiko Nakayama, Ronen Schneider, Agape M. Awad, Anish Nag, Jang Cho, Markus Schueler, Catherine F. Clarke, Rannar Airik, Friedhelm Hildebrandt · 发表于：Journal of the American Society of Nephrology · 年份：2019 · DOI：10.1681/asn.2018060625 · 被引用次数：56 · 研究领域：Coenzyme Q10 studies and effects、Adolescent and Pediatric Healthcare、Biochemical Acid Research Studies

Significance Statement Studies have identified mutations in >55 genes that cause steroid-resistant nephrotic syndrome (SRNS) and localized SRNS pathogenesis to podocytes. The authors previously reported that individuals with mutations in COQ6, a coenzyme Q (CoQ 10 , CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS, and demonstrated that CoQ can reduce kidney dysfunction. In this study, they generated a podocyte-specific Coq6 knockout mouse and showed that abrogating Coq6 in mouse podocytes caused FSGS and proteinuria. In vitro studies revealed an impaired podocyte migration rate in COQ6 knockdown human podocytes. Treating affected mice or cells with 2,4-dihydroxybenzoic acid, an analog of a CoQ precursor molecule, prevented renal dysfunction and reversed migration rate impairment. This suggests a potential therapeutic approach for those cases of human nephrotic syndrome that result from a primary dysfunction in the CoQ 10 biosynthesis pathway. Background Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ 10 , CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function. Methods To study COQ6 function i...