Genetic Mapping Identifies Distinct and Sex-Dependent Genomic Regions Regulating Kidney Development in the HSRA Rat

Variability in nephron number contributes to individual susceptibility to hypertension and chronic kidney disease. The HSRA rat exhibits a high incidence (~75%) of congenital solitary kidney (SK) and reduced nephron endowment. Of the progenitor strains that compose the HSRA genetic background, only the ACI rat exhibits a similar phenotype, though at a much lower incidence (~10%). This suggests that additional genetic modifiers exist in the HSRA. To identify genetic loci influencing kidney status (KS) and nephron number (NN), an F2 population (n=298) was generated by intercrossing HSRA and ACI rats. This effectively fixes the LTR in gene Kit previously identified to be causative to SK in ACI. Quantitative Trait Locus (QTL) analysis identified two significant loci associated with kidney status on chromosomes 13 (10-65 Mb) and 15 (55-75 Mb), containing 497 and 83 genes, respectively. Functional enrichment analysis of the genes within these intervals revealed enrichment for GO terms “lipid export from cell” and “RNA processing” pathways, respectively. Variant analysis of the KS QTL on chromosome 13 did not detect any high-impact variants, but there were 34 moderate and 48 low-impact variants unique to HSRA (not shared with ACI). Within the KS QTL on chromosome 15, 2 high, 8 moderate, and 5 low-impact variants were identified. The high impact variants were predicted to affect Pcdh8 and Setsip. A significant QTL for NN was detected on chromosome 4 (10-31 Mb; 293 genes), and a male-specific QTL was observed on chromosome 10 (53.5-74.5 Mb; 745 genes), suggesting sex-dependent modifiers of NN despite no overall phenotypic difference between sexes in the F2. The chromosome 4 locus contained several developmental genes, including Paxip1, Shh, and a cluster of Sema3 family members, which have been implicated in ureteric bud branching and nephron patterning. Variant analysis identified 13 moderate and 19 low-impact variants within the NN QTL on chromosome 4, with Pclo, Sema3d, and Cd36 among the top candidates. The male-specific chromosome 10 interval contained 2 high, 4 moderate, and 13 low-impact variants. The high impact variants were predicted to affect Zfp207 and Ypel2. Collectively, these findings demonstrate that multiple genomic regions influence kidney development and NN in the HSRA rat model. Planned testing of these candidate genes in iPSC-derived kidney organoids and zebrafish will allow for mechanistic insight during kidney development. This work was supported by R01HL137673 (MRG). The work performed through the UMMC Molecular and Genomics Facility is supported, in part, by funds from the NIGMS, including the Molecular Center of Health and Disease (P20GM144041), Mississippi INBRE (P20GM103476) and Obesity, Cardiorenal and Metabolic Diseases- COBRE (P30GM149404). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.