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

Abstract

BackgroundHypertension 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.MethodsWe induced nephron-specific disruption of the Pkd1 gene in 3-month-old mice and examined them at 4–5 months of age.ResultsKidneys 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.ConclusionsThese 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.

Sex-Dependent Effects of Nephron Ift88 Disruption on BP, Renal Function, and Cystogenesis

“…As stated previously, we reported that nephron Pkd1 gene deficiency also reduces BP prior to cyst formation. 3 This latter study was not powered to examine sex dependency; however, no obvious sexdependent effects were observed (n55-6 of each sex and each genotype). Thus, as mentioned above, the possibility exists that sex-dependent alterations in BP and cystogenesis may vary depending upon the underlying gene mutation.…”

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

“…The authors induced nephron-specific disruption of the Pkd1 in 3-month-old mice and then challenged them with a high salt diet at 4–5months of age. The data suggested that PC1 deficiency in the nephron may exert a salt-wasting effect ( Lakshmipathi et al, 2020 ). Overall, significant ongoing research efforts are devoted to the role of PC1/PC2 in ADPKD development, and not all of the existing controversies have yet been resolved.…”

Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes

“…Therefore, discordance between cyst burden and renal function decline trajectories that could be explained by lower cyst growth and remarkably slowed kidney enlargement in this ADPKD patient. In the present study, it was hypothesized that coexisting ADPKD with masked KS and GS may have a synergistic effect on the stimulation of rapid evolution to ESRD, and their synergistic effect may be the result of regulation of multiple signaling pathways, including vascular disease [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ] (see Figure 2 ).…”