Kidney Week

Abstract: PO1213

Mosaic Inactivation of Pkd1 in Resistance Arteries Leads to Endothelial Dysfunction in Mice

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Dourado, Vivian Christine, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Vivian Christine Dourado

• Dardi, Patrizia, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Patrizia Dardi,

• Rossoni, Luciana V., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Luciana V. Rossoni,

• Onuchic, Luiz F., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Luiz F. Onuchic,

Background

Cardiovascular problems are the leading cause of mortality in autosomal dominant polycystic kidney disease (ADPKD) and hypertension is observed in 50-70% of patients before significant reduction in renal function. The pathogenesis of ADPKD-associated vasculopathy, however, remains largely unclear.

Methods

Mesenteric resistance arteries (MRA) of male normotensive non-cystic Pkd1^+/- mice (HT) and their Pkd1^+/+ controls (WT) as well as in hypertensive cystic Pkd1^flox/flox:Nestin^cre mice (CY) and their non-cystic Pkd1^flox/flox controls (NC) were studied. HT and WT animals were analyzed at the ages of 8-12 and 55-60 weeks and had systolic blood pressure (SBP) recorded by tail plethysmography from 15 to 55 weeks of life, while CY and NC mice were analyzed at 8-12 weeks of life. The endothelium-dependent [acetylcholine (ACh) 10^-9-10^-5 M] and -independent relaxation [sodium nitroprusside (SNP) 10^-11-10^-5 M]; norepinephrine (NE, 10^-9-10^-4 M)- and KCl (120 mM)-mediated contraction were assessed in MRA rings by wire myograph. Structural and mechanical parameters (SMP) were evaluated at 55-60 weeks in HT and WT rings using pressure myograph.

Results

At 8-12 weeks, no significant difference in ACh-induced relaxation was observed in MRA between HT and WT mice. CY mice, on the other hand, displayed lower ACh-induced relaxation compared to NC animals (Maximal response: 44.5±7.7 vs 19.9±6.7%; P<0.05), although this parameter was impaired in NC compared to WT (P<0.0001). SNP-induced relaxation was similar among groups. The contraction induced by NE or KCl did not differ between HT and WT or between CY and NC mice. At 55-60 weeks, vascular reactivity and SMP did not differ in MRA between HT and WT mice. Interestingly, no difference in SBP was identified between these groups.

Conclusion

Mosaic inactivation of both copies of Pkd1 led to endothelial dysfunction in MRA, a phenotype not induced by Pkd1 haploinsufficiency. Aging did not lead to development of hypertension or vascular dysfunction and remodeling in Pkd1-haploinsufficient mice. While our data suggest that the endothelial abnormality observed in these cystic mice may be a primary dysfunction, current investigation is assessing a potential contribution of chronic hypertension.

Funding

• Government Support – Non-U.S.