Abstract
Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of salt transport via the sodium cotransporter NKCC2 in the TAL. At baseline, hepsin-deficient mice accumulate uromodulin, along with hyperactivated NKCC2, resulting in a positive sodium balance and a better adaptation to water deprivation. In conditions of high salt intake, defective uromodulin processing predisposes hepsin-deficient mice to a salt-wasting phenotype, with a decreased salt sensitivity. These modifications are associated with intracellular accumulation of uromodulin, endoplasmic reticulum-stress and signs of tubular damage. These studies expand the physiological role of hepsin and uromodulin and highlight the importance of hepsin-mediated processing of uromodulin for kidney tubule homeostasis and salt sensitivity.
Highlights
Www.nature.com/scientificreports concentrate the urine[9,10,11,12]
In case of high salt exposure, uromodulin excretion dramatically increases in wild-type mice but not in Hlb[320] mice, in which uromodulin accumulates inside thick ascending limb (TAL) cells, creating ER stress and tubular dysfunction
Genomic DNA analysis confirmed a thymine to cytosine substitution at the second nucleotide position in the 3′ splice site of exon 8 of Hpn (Fig. 1a), with only ∼5% residual Hpn mRNA expression detected in Hlb[320] kidneys by RT-qPCR, no RT-PCR product (Fig. 1b), and no hepsin protein detected in the kidney and TAL apical membrane in Hlb[320] mice (Fig. 1c)
Summary
Www.nature.com/scientificreports concentrate the urine[9,10,11,12]. UMOD variants that are associated with hypertension are known to lead to an increase of uromodulin expression and NKCC2 activity in humans[13]. Whether the physiological role of uromodulin is mediated by its cellular processing or apical release into the urine remains unknown. The functional loss of hepsin leads to cellular accumulation of uromodulin, leading to increased activity of NKCC2 and defective NaCl handling in vitro and in vivo. In case of high salt exposure, uromodulin excretion dramatically increases in wild-type mice but not in Hlb[320] mice, in which uromodulin accumulates inside TAL cells, creating ER stress and tubular dysfunction. These studies expand the physiological role of hepsin and reveal the importance of hepsin-mediated processing of uromodulin for salt handling by the kidney
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