Treatment with 2,4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific <i>Coq6</i> Knockout Mice.
basic_science · Level V
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- Record sourced from PubMed, PMID 30737270.
- Also identified by DOI 10.1681/ASN.2018060625 and PMC identifier 6405149.
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Abstract
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<sub>10</sub>, CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function. To study <i>COQ6</i> function in podocytes, we generated a podocyte-specific <i>Coq6</i> knockout mouse (<i>Coq6<sup>podKO</sup></i> ) model and a transient siRNA-based <i>COQ6</i> knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in <i>COQ6</i> knockdown podocytes and control podocytes. We also randomly assigned 5-month-old <i>Coq6<sup>podKO</sup></i> mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States. Abrogation of <i>Coq6</i> in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria). <i>In vitro</i> studies revealed an impaired podocyte migration rate in <i>COQ6</i> knockdown human podocytes. Treating <i>Coq6<sup>podKO</sup></i> mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of <i>Coq6<sup>podKO</sup></i> mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated <i>Coq6<sup>podKO</sup></i> mice, half of which died by 10 months of age. These findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ<sub>10</sub> biosynthesis pathway.