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Nephron‐specific disruption of Cullin3 causes salt‐sensitive hypotension (1136.7)
Author(s) -
McCormick James,
Terker Andrew,
McCully Belinda,
Meermeier Nicholas,
Yarbrough Bethzaida,
Park Hae,
Yang Chaoling,
Singer Jeffrey,
Ellison David
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1136.7
Subject(s) - medicine , endocrinology , nephron , blood pressure , biology , chemistry , kidney
Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in genes that regulate activity of the renal sodium chloride cotransporter (NCC), including the kinases WNK1 and WNK4, and Cullin3 (Cul3) and KLHL3, members of a ring ubiquitin ligase complex. To examine the physiological roles of Cul3 and how mutations in it cause FHHt, we generated Cul3‐/‐ mice. An inducible system that disrupts Cul3 specifically along the entire nephron was used since complete Cul3 disruption is embryonic lethal. Western blots showed nearly complete absence of Cul3 in Cul3‐/‐ kidneys. Cul3‐/‐ mice displayed volume contraction, hypochloremia and alkalosis, and elevated plasma aldosterone. Blood pressure, measured by radiotelemetry, was similar in both groups on normal NaCl diet, but during NaCl restriction, Cul3‐/‐ mice displayed a progressive reduction in blood pressure. After 9 days, the 24h mean blood pressure pressure was 18 mmHg lower in Cul3‐/‐ mice. Expression of total and phospho‐NCC were slightly elevated in Cul3‐/‐ mice on normal diet, but dietary NaCl restriction did not cause their levels to increase to the same extent as it did in wild types. WNK4 expression was dramatically increased in Cul3‐/‐ mice on normal and low NaCl diets, while WNK1 and WNK3 were slightly elevated. In conclusion, these data suggest that loss of Cul3 activity along the nephron does not mimic FHHt, but leads to a mild salt‐wasting phenotype. Grant Funding Source : KO1 DK076617