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

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.

Molecular regulation of NKCC2 in blood pressure control and hypertension.

PURPOSE OF REVIEW: The apical Na/K/2Cl cotransporter (NKCC2) mediates NaCl reabsorption by the thick ascending limb, contributing to maintenance of blood pressure (BP). Despite effective NKCC2 inhibition by loop diuretics, these agents are not viable for long-term management of BP due to side effects. Novel molecular mechanisms that control NKCC2 activity reveal an increasingly complex picture with interacting layers of NKCC2 regulation. Here, we review the latest developments that shine new light on NKCC2-mediated control of BP and potential new long-term therapies to treat hypertension. RECENT FINDINGS: Emerging molecular NKCC2 regulators, often binding partners, reveal a complex overlay of interacting mechanisms aimed at fine tuning NKCC2 activity. Different factors achieve this by shifting the balance between trafficking steps like exocytosis, endocytosis, recycling and protein turnover, or by balancing phosphorylation vs. dephosphorylation. Further molecular details are also emerging on previously known pathways of NKCC2 regulation, and recent in-vivo data continues to place NKCC2 regulation at the center of BP control. SUMMARY: Several layers of emerging molecular mechanisms that control NKCC2 activity may operate simultaneously, but they can also be controlled independently. This provides an opportunity to identify new pharmacological targets to fine-tune NKCC2 activity for BP management.

Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2).

The Na-K-2Cl cotransporter (NKCC2; BSC1) is located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL). NKCC2 facilitates ∼20-25% of the reuptake of the total filtered NaCl load. NKCC2 is therefore one of the transport proteins with the highest overall reabsorptive capacity in the kidney. Consequently, even subtle changes in NKCC2 transport activity considerably alter the renal reabsorptive capacity for NaCl and eventually lead to perturbations of the salt and water homoeostasis. In addition to facilitating the bulk reabsorption of NaCl in the TAL, NKCC2 transport activity in the macula densa cells of the TAL constitutes the initial step of the tubular-vascular communication within the juxtaglomerular apparatus (JGA); this communications allows the TAL to modulate the preglomerular resistance of the afferent arteriole and the renin secretion from the granular cells of the JGA. This review provides an overview of our current knowledge with respect to the general functions of NKCC2, the modulation of its transport activity by different regulatory mechanisms, and new developments in the pathophysiology of NKCC2-dependent renal NaCl transport.