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Abstract: TH-OR074

Haploinsufficiency of Transcription Factor ETS-1 Improves Renal Autoregulation in Dahl Salt Sensitive Rats

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Feng, Wenguang, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Guan, Zhengrong, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Xing, Dongqi, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Li, Xingsheng, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Ying, Wei-zhong, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Inscho, Edward W., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Sanders, Paul W., University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

The mechanisms underlying the susceptibility to hypertension-associated kidney injury are not well defined. Previously, we showed that the transcription factor ETS-1 mediates glomerular injury in Dahl Salt Sensitive (SS) rats. Hypertensive SS rats with a single functioning ETS-1 gene (ES, developed with zinc-finger nuclease (ZFN) technology), exhibit less glomerular injury. Because renal autoregulation is critical for protecting glomeruli from arterial hypertension, we hypothesized that ETS-1 transactivity is involved in afferent arteriolar autoregulatory behavior.

Methods

SS and ES rats were maintained on either a 0.3% (LS SS and LS ES) or a 4% NaCl diet (HS SS and HS ES) for one week.

Results

Assessment of serum creatinine and albuminuria revealed that renal dysfunction was present in the hypertensive HS SS rats, but was abrogated in the HS ES rats despite similar increases in telemetry mean blood pressures. Afferent arteriolar autoregulation was assessed using the in vitro blood-perfused juxtamedullary nephron preparation. Average baseline diameter of afferent arterioles were similar across the four groups of rats (P>0.05). Afferent arterioles from LS SS and LS ES rats exhibited normal autoregulatory behavior. Decreasing renal perfusion pressure from 100 to 65 mmHg increased arteriole diameter to 118 ± 2% and 119 ± 4% of baseline diameter, respectively. Stepwise increases in perfusion pressure to 170 mmHg decreased arteriolar diameter to 75.4 ± 3% and 72.9 ± 4% respectively. In contrast, pressure-mediated afferent arteriolar responses were markedly impaired in HS SS rats. Baseline diameter averaged 15.1 ± 1.2 µm and remained between 107 ± 3% and 89 ± 4% (p< 0.05 vs. LS SS) of baseline over the 65-170 mmHg pressure range tested. Importantly, renal autoregulation was significantly improved in HS ES rats. Baseline diameter averaged 15.6 ± 0.9 µm, and decreasing renal perfusion pressure from 100 to 65 mmHg resulted in a diameter increase to 114 ± 2% while increasing perfusion pressure to 170 mmHg resulted in a pressure-dependent vasoconstriction to 73 ± 3% (P<0.05 vs SS HS).

Conclusion

These results show that ETS-1 influences renal arteriolar autoregulation in SS rats and that impaired autoregulation may contribute to hypertension-induced kidney injury in SS rats.

Funding

  • Veterans Affairs Support