Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

Jing Wu, Larry N. Agbor, Shi Fang, Masashi Mukohda, Anand R. Nair, Pablo Nakagawa, Avika Sharma, Donald A. Morgan, Justin L. Grobe, Kamal Rahmouni, Robert M. Weiss, James A. McCormick, Curt D. Sigmund

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Aims: Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Methods and results: Mice selectively expressing a peroxisome proliferator-activated receptor γdominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. Conclusion: We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γimpairment.

Original languageEnglish (US)
Pages (from-to)308-319
Number of pages12
JournalCardiovascular research
Volume117
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Hypertension
  • PPARγ
  • Renal function
  • Salt
  • Smooth muscle
  • Vasodilation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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