Abstract MP14: A K572Q Mutation in Gamma-adducin Is Responsible for the Impaired Myogenic Response and Autoregulation of Renal and Cerebral Blood Flow in FHH Rats

Abstract

The FHH rat is a genetic model of hypertension induced CKD, but the genes and pathways involved are unknown. We recently reported that the myogenic response of the renal and cerebral arteries is impaired in FHH rats and it was restored in a FHH.1BN congenic strain in which a small region of Chr. 1 containing 15 genes, including gamma-Adducin (Add3), from BN rats was transferred into the FHH background. We further identified a K572Q mutation in Add3 in FHH versus FHH.1BN rat. The present study examined the contribution of Add3 to the impaired myogenic reactivity using Add3 transgenic and KO rats. The diameter of the middle cerebral artery (MCA) decreased by 20-30% in SD, FHH.1BN and FHH.Add3 transgenic rats when perfusion pressure was increased from 40 to 140 mmHg. In contrast, the MCA of FHH and SD.Add3 knockout rats did not constrict. The myogenic response of the MCA is also impaired in MNS rats that share the same mutation in Add3 as in FHH rat and this phenotype was complemented in a F1 cross of FHH and MNS strain. Autoregulation of CBF was impaired in FHH rats and rose by 99 ± 7% when MAP was increased from 100 to 190 mmHg and was restored in FHH.Add3 and FHH.1BN rats. Similarly, the diameter of Af-art of FHH, MNS and a F1 cross of FHH and MNS rat increased in response to increase in perfusion pressure but decreased in FHH.1BN rats that have wild type Add3. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1BN rats. Pgc estimated from the stopflow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in the congenic strain. FHH rats developed severe renal injury and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1BN and FHH.Add3 rats. BK current in VSMC isolated from the MCA was 5-fold higher in FHH vs. FHH.1BN rats. Administration of IBTX normalized the elevated BK channel current and restored the myogenic response in FHH rats but it had little effect in FHH.1BN. These results indicate that the K572Q mutation in Add3 plays a causal role in the impaired myogenic response and autoregulation of renal and cerebral circulation in FHH rats and may contribute to the development of renal and cerebral end organ damage with aging and after the onset of hypertension.