Abstract: SA-PO374

A Recessive K572Q Mutation in Gamma-Adducin Plays a Causal Role in Impaired Renal Vascular Reactivity in FHH and MNS Rats

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Zhang, Chao, University of Mississippi Medical Center , Jackson, United States
  • Ge, Ying, University of Mississippi Medical Center , Jackson, Mississippi, United States
  • Zhu, Tongyu, Zhongshan Hospital, Fudan University, Shanghai, China
  • Mims, Paige N, University of Mississippi Medical Center , Jackson, Mississippi, United States
  • Fan, Fan, University of Mississippi Medical Center , Jackson, Mississippi, United States
  • Roman, Richard J., University of Mississippi Medical Center , Jackson, Mississippi, United States
Background

The Fawn-Hooded hypertensive (FHH) rat is a genetic model for studying hypertension induced renal disease, however the causal genes involved are unclear. We previously reported that the transfer of a small region in Chr. 1 of Brown-Norway (BN) rats which contains 15 genes, including gamma-Adducin (Add3), into the FHH background could restore the impaired renal microvascular function in FHH rats. Our further work identified a K572Q mutation in Add3 in FHH rats as a potential candidate variant in the pathogenesis of renal disease.

Methods

The present study examined the role of the K572Q mutation of Add3 in the autoregulation of renal blood flow (RBF) and the myogenic response of renal afferent arteriole (af-art) by using Add3 transgenic and knockout (KO) rats.

Results

RBF increased by 21.5 ± 3.0% in SD. Add3 KO rats (n=7) when mean arterial pressure (MAP) was increased from 100 to 150 mmHg. In contrast, RBF only increased by 3.5 ± 0.9% in wildtype (wt) SD rats (n=13). The diameter of the renal af-art decreased by 13 ± 0.8% in SD rats when perfusion pressure was increased from 60 to 120 mmHg, but it increased in by 5.0 ± 0.6% in the SD.Add3 KO rats. The myogenic response of af-arts in FHH rats was markedly impaired and increased by 8 ± 1.2% when the pressure was increased by from 60 to 120 mmHg. The myogenic response was restored, and the diameter of Af-art decreased by 12 ± 0.7% and 7 ± 1.0% in FHH. 1BN congenic rats (n=27) and Add3 transgenic FHH rats that express wt-Add3. RBF increased by 35.1 ± 3.0% when MAP was increased from 100 to 150 mmHg in FHH rats (n=15) versus only 7.5 ± 1.7% and 6.0+ 1.3% in FHH.1BN or a F1 cross of FHH and FHH.1BN rats (n=8) and in Add3 transgenic FHH rats that express the wt-Add3 gene. The myogenic response of Af-art and autoregulation of RBF were also impaired in MNS rats (n=6) that carry the same K572Q mutation in Add3 as FHH rats. These phenotypes were complemented in an F1 of cross of FHH and MNS rats (n=7), but the myogenic response and autoregulation of RBF were restored in an F1 cross of FHH and FHH.1BN rats with one copy of wt-Add3.

Conclusion

There results suggest that the recessive K572Q mutation of Add3 in FHH and MNS rats plays a causal role in renal microvascular dysfunction that may contribute to the development of proteinuria and chronic kidney disease in these models.

Funding

  • NIDDK Support