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Abstract: SA-PO620

Congenic Substitution to Uncover the Genetic Pathway of Hypertensive Renal Injury

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

  • Doris, Peter A., UNIVERSITY OF TEXAS HOUSTON, Houston, Texas, United States
  • Braun, Michael C., TCH/ BCM, Houston, Texas, United States
  • Hicks, John, Texas Children''s Hospital, Houston, Texas, United States
  • Dhande, Isha, University of Texas Health Science Center at Houston, Houston, Texas, United States
Background

The SHR-A3 line of the spontaneously hypertensive rat experienes progressive renal injury (RI). Susceptibility arises from natural gnetic variaiton and contrasts with injury resistant SHR-B2. These two lines are 87% genetically identical. SHR-A3 has higher blood pressure (BP) than SHR-B2. We have mapped a locus responsible to an 8MB block on chr17. Here we assess whether a congenic line (CL) in which this block is transferred from SHR-B2 into SHR-A3 experiences different levels of BP and RI than SHR-A3. The SHR-A3 and SHR-B2 genomes are most divergent in the immunoglobulin heavy chain (IgH). We created a CL substituting the SHR-B2 IgH locus into SHR-A3 and assesssed the effect on BP and RI. Finally we have created a bicongenic (2CL) line containing both these SHR-B2 loci within the SHR-A3 background.

Methods

CLs were created by backcrossing using genetic markers to identify those regions of the genome at which SHR-A3 and SHR-B2 differ. Blood pressure was measured by telemetry. Renal injury was assessed histologically in paraffin-embedded tissue stained with Periodic acid-Schiffs stain.

Results

Congenic substitution of the chr17 locus was associated with a reduction in blood pressure to a level that was significantly below SHR-A3, but not different from SHR-B2. At 40wks of age, glomerular injury (GI) was indistinguishable in this CL from SHR-B2. Tubulointerstital injury (TI) in the CL was intermediate, but significantly below SHR-A3. Congenic substituion of the IgH locus from SHR-B2 into the SHR-A3 background had no effect on BP. At 40wks, this CL also had GI indistinguishable from SHR-B2 and TI intermediate between SHR-A3 and SHR-B2. In the 2CL, GI and TI were both reduced to the SHR-B2 level.

Conclusion

RI in SHR-A3 appears to result from at least two genetic loci. One is an 8Mbase block on chromosome 17 that results in hgiher blood pressure in SHR-A3 than SHR-B2. The other is the immunoglobulin heavy chain, indicating that genetic variation in germ-line antibody sequences may contribue to the pathogenesis of renal injury in this model. The combined effect of these loci eliminates histologically assessed RI, resulting in animals that are 99.5% geneticall identical to SHR-A3, but resistant to renal injury.

Funding

  • NIDDK Support