Nephron-Segment Composition and Apparent Fatty Acid Oxidation Suppression in Pkd1KO+Glis3KO Kidneys

We read with interest the recent JASN article by Wei et al. describing tubule-restricted Glis3 inactivation exacerbating cyst progression in Pkd1-deficient mice and identifying a prominent downregulation of fatty acid β-oxidation genes in Pkd1KO+Glis3KO kidneys (Figure 4E).1 The genetic interaction and multiomic integration are compelling. We wondered whether the whole-kidney (bulk) RNA-Seq signal for β-oxidation suppression might be influenced, at least in part, by nephron-segment composition. Many β-oxidation genes emphasized in Figure 4E—Acsm2/Acsm3, Acadl, Ech1, Hadh, Slc27a2, Acox1, and Amacr—are strongly proximal tubule–enriched in segment-resolved mouse transcriptomes.2 Even small differences in proximal tubule representation (or nonepithelial content) between Pkd1KO and Pkd1KO+Glis3KO could therefore affect the apparent direction and magnitude of the “fatty acid metabolic process” gene set. Could the authors indicate whether canonical segment markers (e.g., Lrp2/Slc34a1 for proximal tubule, Slc12a1 for thick ascending limb, Aqp2 for collecting duct) are comparable across genotypes at P49? A marker-based sensitivity analysis or reference deconvolution using published segment-resolved transcriptomes2 would also help establish that β-oxidation downregulation reflects transcriptional rewiring within tubule epithelium. Given evidence that fatty acid oxidation defects are present in orthologous autosomal dominant polycystic kidney disease models3 and can be modified by peroxisome proliferator–activated receptor alpha activation,4 such clarification could further sharpen the mechanistic and translational implications of this important work.