Genetic basis of altered myogenic response and renal injury in FHH rats

Abstract

This study examined the effect of substitution of a 2.6Mb segment from Brown Norway (BN) rat Chr 1 into the Fawn Hooded Hypertensive (FHH) rat genetic background on autoregulation of renal blood flow (RBF) and development of renal injury. FHH rats exhibited poor autoregulation of RBF and GFR rose by 60% when renal perfusion pressure (RPP) was increased from 100 to 150 mmHg while the FHH.1BN congenic strain exhibited perfect autoregulation of RBF. Protein excretion rose from 51±5 to 259±41 mg/day in 9 to 21 week FHH rats but only increased to 147±24 mg/day in the FHH.1BN congenic strain. Diameter of isolated perfused afferent arterioles from FHH rats did not change significantly when transmural pressure was increased from 60 to 140 mmHg. In contrast, diameter of the congenic decreased 19.4% with the same pressure increase. Patch clamping experiments indicate that large conductance Calcium activated K+ channel (BK) current was 5 fold greater in vascular smooth muscle (VSM) cells isolated from renal vessels of FHH rats than the congenic strain. This data indicates that the gene responsible for restoring autoregulation of RBF lies within this 2.6 Mb region containing 11 genes and transfer of this region restores the myogenic response and slows the progression of renal disease. The impaired myogenic response is likely due to hyperpolarization of VSM cells due to increased BK channel activity. NIH HL36279, DK079306 and HL69321.