The Urinary Excretion of Uromodulin is Regulated by the Potassium Channel ROMK.

Uromodulin, the most abundant protein in normal urine, is produced by cells lining the thick ascending limb (TAL) of the loop of Henle. Uromodulin regulates the activity of the potassium channel ROMK in TAL cells. Common variants in KCNJ1, the gene encoding ROMK, are associated with urinary levels of uromodulin in population studies. Here, we investigated the functional link between ROMK and uromodulin in Kcnj1 knock-out mouse models, in primary cultures of mouse TAL (mTAL) cells, and in patients with Bartter syndrome due to KCNJ1 mutations. Both global and kidney-specific Kcnj1 knock-out mice showed reduced urinary levels of uromodulin paralleled by increased levels in the kidney, compared to wild-type controls. Pharmacological inhibition and genetic deletion of ROMK in mTAL cells caused a reduction in apical uromodulin excretion, reflected by cellular accumulation. In contrast, NKCC2 inhibition showed no effect on uromodulin processing. Patients with Bartter syndrome type 2 showed reduced urinary uromodulin levels compared to age and gender matched controls. These results demonstrate that ROMK directly regulates processing and release of uromodulin by TAL cells, independently from NKCC2. They support the functional link between transport activity and uromodulin in the TAL, relevant for blood pressure control and urinary concentrating ability.

Genetic variant rs623011 (17q24.3) associates with non-familial thyrotoxic and sporadic hypokalemic paralysis.

BACKGROUND: A recent genome-wide association study of Thai patients with thyrotoxic periodic paralysis (TPP) identified a novel genetic variant rs623011 located in chromosome 17q24.3, which may potentially reduce the transcription of Kir2.1 and total Kir current. PURPOSE: The aim of this study was to evaluate whether this genetic variant was present in Chinese patients with TPP and sporadic periodic paralysis (SPP), the second leading cause of non-familial hypokalemic periodic paralysis (hypoKPP) in Asia. METHODS: Ninety patients with TPP, 61 SPP, and 100 age and sex-matched healthy subjects were performed. Genomic DNA was isolated from blood leukocytes and analysis of rs623011 was performed by polymerase chain reaction and direct sequencing. RESULTS: Compared with normal control, the frequency of the risk allele A of rs623011 was significantly higher in both TPP and SPP patients (73.9% versus 53.5%, p=0.001; 82.0% versus 53.5%, p<0.001, respectively) with the Odds ratios (95% confidence interval) 2.426 (1.348-4.369) and 4.488 (2.265-8.891), respectively. The frequency of the A allele of rs623011 was similar between TPP and SPP. CONCLUSIONS: TPP and SPP have the same susceptible gene variant rs623011 and may share the pathogenic mechanism of reduced Kir current in skeletal muscle independent of thyroid hormone.