SODIUM
The kidneys filter roughly 180 liters of fluid per day, including 1.4 kilograms of sodium, almost as much as is present in a large box of pickling salt! The kidney’s nephron reabsorbs all but ~1.5 teaspoons, preventing loss in the urine. The epithelial sodium channel (ENaC) in the nephron contributes to reabsorption of sodium.
We are studying regulation of the epithelial sodium channel (ENaC) and its influence upon total body sodium, bodily fluid content, and blood pressure. Key regulatory mechanisms under investigation include:
Genetic polymorphisms in humans: We examined whether humans with salt-sensitive hypertension carried genetic variation in ENaC that influences regulation of the channel. In a cohort of individuals with salt-sensitive blood pressure, we found several polymorphisms that influence channel activity. PMID: 27582106
Functionally relevant, non-synonymous human ENaC polymorphisms superimposed upon the crystal structure of the ENaC homologue, ASIC.
Activation of ENaC by extracellular proteases: We hypothesize that, in damaged kidneys, blood stream proteases, such as plasmin, leaked into the kidney tubules can activate ENaC, increasing retention of sodium by the kidney. We found that urinary levels of plasmin and its precursor, plasminogen, predicted incident hypertension in subjects with type I diabetes. PMID: 30450470
We hypothesize that, in patients with leakage of plasma proteins into the urine, plasmin from the blood stream activates ENaC, contributing to the sodium retention, edema, and high blood pressure these patients experience.
We found that, in type I diabetes, increased urinary plasmin levels predicted risk of developing hypertension years later. Stratification above represents top tertile of urinary plasmin(ogen), normalized to urinary creatinine, versus lower two tertiles.
Unfortunately, these studies were unable to demonstrate an association between urinary plasmin and hypertension independently of other urinary proteins. A strong case for cause and effect could not be established. Therefore, we are now working with genetic models to understand the role of proteolytic activation of ENaC in hypertension associated with kidney disease.
The observation that proteinuric kidney disease is associated with increased ENaC activity suggests that pharmacologic blockade of this channel may be effective in treating fluid retention and high blood pressure in patients with protein in the urine. We attempted a small clinical trial examining this hypothesis. We found that diabetic patients with proteinuria are quite sensitive to amiloride, which blocks ENaC. A subset of patients given amiloride experienced sudden decrease in kidney function that improved when they were given fluids (PMID: 28890943). This is consistent with the hypothesis that ENaC contributes to sodium retention in proteinuric kidney disease, but suggests that blockers of ENaC activity must be used very cautiously in these patients, as discussed here: PMID: 30178569.
Further studies are examining whether ENaC’s role in sodium transport influences bone health or immune function.