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Abstract: FR-PO403

Genetic Regulation of Diabetic Kidney Disease Traits and Transcriptome Signature in Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wu, Xiuju, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Basgen, John M., Charles Drew University, Minnetonka, Minnesota, United States
  • Merkurjev, Daria, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Lusis, Aldons J., David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Nicholas, Susanne B., David Geffen School of Medicine at UCLA, Los Angeles, California, United States
Background

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. Thus far, the genetic factors contributing to hallmark features of DKD remain poorly understood. Our goal was to assess DKD and associated molecular markers in an intercross between two strains of mice differing in albuminuria on the background of the diabetes-inducing Ins2Akita mutation.

Methods

We generated F2 mice from a cross between maternal CBA/J and paternal C57BL/6J-Ins2Akita mice. We measured albumin-to-creatinine ratio (ACR) on 24-h urine from F2 mice at age 7 and 20 weeks. Kidney morphometry was quantified by light and electron microscopy at 20 weeks. We performed RNA sequencing on kidney cortex to identify transcripts associated with physiologic and structural traits. Linkage analysis identified causal loci of physiologic and molecular traits.

Results

We observed 20-fold variation in ACR among 87 diabetic F2 mice at age 20 weeks. Plasma glucose (p=1.7×10-6), kidney weight (p=1.0×10-6), glomerular volume (p=2.1×10-11), glomerular basement membrane width (p=2.2×10-5), total mesangial cell (1×10-2) and total mesangial matrix (p=1.5×10-4) increased significantly in diabetic F2 mice versus non-diabetic mice. We detected a significant quantitative trait locus for ACR on chromosome 4 (LOD=3.79, p=0.030) and a locus for volume fraction of mesangial cell and total mesangial cell on chromosome 14, LOD=3.79, p=0.031. We identified regulatory pathways enriched for oxidative stress (p=1.23×10-14), fatty acid metabolism (p=6.86×10-11) and mitochondrial function (p=4.51×10-12) associated with ACR.

Conclusion

The study identified a genetic basis for increases in volume fraction of mesangial cell, total mesangial cell and ACR, and regulatory pathways associated with oxidative stress, fatty acid metabolism and mitochondrial function in DKD. The study provides further insight to the genetic determination of DKD traits.

Funding

  • Other NIH Support