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Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

Sabrine Hassane1, Nanna Claij, Martine Jodar

  • 1Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|September 22, 2010
PubMed

Insights

Autosomal dominant polycystic kidney disease (ADPKD) involves cyst formation and cardiovascular issues. This study found that disrupting the PKD1 gene in vascular smooth muscle cells alters hypertension adaptation but does not cause blood vessel abnormalities.

Area of Science:

  • Genetics
  • Cardiovascular Biology
  • Nephrology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing cysts in kidneys, liver, and pancreas, along with cardiovascular complications.
  • Mutations in PKD1 or PKD2 genes are the primary cause of ADPKD.
  • Previous studies in mice with reduced Pkd1 expression showed dissecting aneurysms and media thickening.

Purpose of the Study:

  • To investigate the specific role of the PKD1 gene in vascular smooth muscle cells (SMCs) by selectively disrupting it.
  • To determine if Pkd1 disruption in SMCs leads to vascular abnormalities or affects cardiovascular responses.
  • To understand the impact of Pkd1 gene function in SMCs on adaptation to hypertension.

Main Methods:

  • Generated SM22-Pkd1(del/del) mice with floxed Pkd1 gene deletion driven by the SM22 promoter in SMCs.
  • Confirmed Cre activity and Pkd1 gene reduction in the aorta using X-gal staining and quantitative PCR.
  • Performed histopathological analysis for cyst formation and isometric myography to assess vascular function and response to hypertension stimuli (angiotensin II).

Main Results:

  • Histopathology revealed cyst formation in pancreas, liver, and kidneys due to extravascular Cre activity.
  • No gross structural blood vessel abnormalities were observed in mice with Pkd1 disruption in SMCs or SMCs/endothelial cells (ECs).
  • SM22-Pkd1(del/del) mice exhibited significantly reduced heart rate decrease during angiotensin II-induced hypertension, indicating altered adaptation.

Conclusions:

  • Selective disruption of Pkd1 in vascular smooth muscle cells does not cause spontaneous vascular abnormalities.
  • The study demonstrates that Pkd1 in SMCs plays a role in the body's adaptation to hypertension.
  • These findings highlight a novel function of Pkd1 in cardiovascular regulation beyond its known role in cystogenesis.

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