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Abstract: TH-PO867

Genetic and Functional Investigation of Nephron Number on Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Cobb, Meredith B., University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Showmaker, Kurtis C., University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Wu, Wenjie, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Attipoe, Esinam M., University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Johnson, Ashley Colleen, University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Garrett, Michael R., University of Mississippi Medical Center, Jackson, Mississippi, United States
Background

Low nephron number has been linked with susceptibility to hypertension and CKD, but a clear connection between nephron number and hyperglycemic renal injury is lacking. Our current work seeks to investigate the association between nephron deficiency and the development of diabetic CKD using a unique model of nephron deficiency, the HSRA rat. HSRA are born with a single kidney 50-75% of the time while the remaining pups are born with two. The model provides a unique advantage for direct comparison of congenital one-kidney, nephron-deficient animals (HSRA-S, ~20,400 nephrons), nephrectomized two-kidney animals (HSRA-UNX, ~25,100 nephrons) and two-kidney littermates (HSRA-C, ~50,000 nephrons). Previous work demonstrated that HSRA-S develops increased renal dysfunction with age compared to HSRA-UNX and HSRA-C, which is greatly exacerbated in the presence of DOCA hypertension. This suggests that even slight nephron differences (-S vs –UNX) are important driver of elevated blood pressure, kidney injury and accelerate decline in kidney function.

Methods

To investigate the impact of hyperglycemia on renal injury in the HSRA rat, streptozotocin (STZ) was administered at 9 weeks of age in all three groups; animals were followed for 15 weeks.

Results

Despite overt hyperglycemia (350-450 mg/dl), the diabetic groups did not develop increased proteinuria compared to their non-diabetic counterparts, contrary to the impact of second insult of hypertension.

Conclusion

Current studies are investigating the impact of hyperglycemia after overt injury (“late insult”) in HSRA-S (week >24) is observed. Additionally, studies to revisit the “early insult” of hyperglycemia with the addition of modest hypertension (130 mmHg) via DOCA have begun. To better understand the underlying genetic cause of renal agenesis, altered nephrogenesis in the solitary kidney, and perhaps the differential response of injury to hypertension and hyperglycemia, genetic linkage analysis has been initiated in the HSRA model to map the quantitative trait loci/modifier genes. This work, along with completed whole genome sequencing and annotation of HSRA genome will hopefully identify new genes/pathways relevant to nephrogenesis and provide insight into differences in the interaction between nephron number and secondary insults of hypertension and hyperglycemia.

Funding

  • Other NIH Support