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Kidney Week

Abstract: SA-PO392

RNA-Sequencing Based Approach to Identify Novel Pathways Regulating Atrophic and Hypertrophic Renal Remodeling

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Paterson, Mark, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Kriegel, Alison J., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

There is a great need to understand the mechanisms that regulate renal survival to preserve tubular function in patients with various forms of renal disease. In previous studies in Sprague Dawley rats we observed that excision of 2/3 of the left kidney resulted in atrophy of the remnant kidney, while excisions of both 2/3 of the left kidney and the entire right kidney resulted a robust hypertrophy of the remnant kidney from 5 to 7 weeks after surgery. The sole difference between these models is the presence or absence of the right kidney, providing a well-controlled opportunity to explore mechanisms that promote survival and senescence. The goal of this study was to identify molecular pathways that regulate renal hypertrophy and atrophy by the contrasting mRNA expression changes within each model. We hypothesized that transcript analysis would reveal unique expression profiles, highlighting the distinct stress response in each state.

Methods

We collected remnant kidneys from the atrophic and hypertrophic models (n=6/group), as well as the left kidney in sham operated controls 6 weeks after respective surgery (n=5). Next-generation RNA sequencing of these samples was performed, and subsequent statistical and Ingenuity Pathway Analysis (IPA) was completed.

Results

Comparison of RNA expression in atrophic and hypertrophic remnant kidneys against sham control kidneys identified 1112 and 867 differentially expressed transcripts (DET; adjusted p-value <0.05), respectively. In the atrophic kidney nearly 1/3 of the DET were downregulated (32.4%). IPA revealed an enrichment of numerous downregulated transcripts encoding proteins within electron transport chain and amino acid synthesis pathways, among others, consistent with changes expected in senescent tissue. The transcripts altered in the hypertrophic kidney were overwhelmingly upregulated (98.5%), enriched in pathways related to hypertrophic growth and many others. This analysis also revealed novel upstream pathways enriched with differentially expressed transcripts that will be explored to nominate therapeutic targets for functional evaluation in these models.

Conclusion

Together our data suggest that these remnant kidney models will allow us to appropriately model processes relevant to renal hypertrophy and renal atrophy and indentify molecular pathways involved with morphological and functional changes.