Dataset Information

Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2-Mediated Blood Pressure Reduction Independent of Cystogenesis.

ABSTRACT:

Background

Hypertension often occurs before renal function deteriorates in autosomal dominant polycystic kidney disease (ADPKD). It is unknown whether the Pkd1 gene product polycystin-1-the predominant causal factor in ADPKD-itself contributes to ADPKD hypertension independent of cystogenesis.

Methods

We induced nephron-specific disruption of the Pkd1 gene in 3-month-old mice and examined them at 4-5 months of age.

Results

Kidneys from the Pkd1 knockout mice showed no apparent renal cysts, tubule dilation, or increased cell proliferation. Compared with control mice, Pkd1 knockout mice exhibited reduced arterial pressure during high salt intake; this associated with an increased natriuretic, diuretic, and kaliuretic response during the first 2-3 days of salt loading. The lower arterial pressure and enhanced natriuresis during high salt loading in Pkd1 knockout mice were associated with lower urinary nitrite/nitrate excretion and markedly increased urinary PGE₂ excretion, whereas GFR, plasma renin concentration, and urinary endothelin-1 excretion were similar between knockout and control mice. Kidney cyclooxygenase-2 protein levels were increased in Pkd1 knockout mice during high salt intake; administration of NS-398, a selective cyclooxygenase-2 inhibitor, abolished the arterial pressure difference between the knockout and control mice during high salt intake. Total kidney Na⁺/K⁺/2Cl^- cotransporter isoform 2 (NKCC2) levels were greatly reduced in Pkd1 knockout mice fed a high salt diet compared with controls.

Conclusions

These studies suggest that nephron polycystin-1 deficiency does not itself contribute to ADPKD hypertension and that it may, in fact, exert a relative salt-wasting effect. The work seems to comprise the first in vivo studies to describe a potential physiologic role for nephron polycystin-1 in the absence of cysts, tubule dilation, or enhanced cell proliferation.

SUBMITTER: Lakshmipathi J

PROVIDER: S-EPMC7269346 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:We developed a new model of hypertension care for non-Hispanic black men that links health promotion by barbers to medication management by American Society of Hypertension-certified pharmacists and demonstrated efficacy in a 6-month cluster-randomized trial. The marked reduction in systolic blood pressure (BP) seen at 6 months warranted continuing the trial through 12 months to test sustainability, a necessary precondition for implementation research. METHODS:We enrolled a cohort of 319 black male patrons with systolic BP ?140 mm?Hg at baseline. Fifty-two Los Angeles County barbershops were assigned to either a pharmacist-led intervention or an active control group. In the intervention group, barbers promoted follow-up with pharmacists who prescribed BP medication under a collaborative practice agreement with patrons' primary care providers. In the control group, barbers promoted follow-up with primary care providers and lifestyle modification. After BP assessment at 6 months, the intervention continued with fewer in-person pharmacist visits to test whether the intervention effect could be sustained safely for 1 year while reducing pharmacist travel time. Final BP and safety outcomes were assessed in both groups at 12 months. RESULTS:At baseline, mean systolic BP was 152.4 mm?Hg in the intervention group and 154.6 mm?Hg in the control group. At 12 months, mean systolic BP fell by 28.6 mm?Hg (to 123.8 mm?Hg) in the intervention group and by 7.2 mm?Hg (to 147.4 mm?Hg) in the control group. The mean reduction was 20.8 mm?Hg greater in the intervention (95% CI, 13.9-27.7; P<0.0001). A BP <130/80 mm?Hg was achieved by 68.0% of the intervention group versus 11.0% of the control group ( P<0.02). These new 12-month efficacy data are statistically indistinguishable from our previously reported 6-month data. No treatment-related serious adverse events occurred in either group over 12 months. Cohort retention at 12 months was 90% in both groups. CONCLUSIONS:Among black male barbershop patrons with uncontrolled hypertension, health promotion by barbers resulted in large and sustained BP reduction over 12 months when coupled with medication management by American Society of Hypertension-certified pharmacists. Broad-scale implementation research is both justified and warranted. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02321618.