Hepsin-mediated Processing of Uromodulin is Crucial for Salt-sensitivity and Thick Ascending Limb Homeostasis

Olinger, Eric; Lake, Jennifer; Sheehan, Susan; Schiano, Guglielmo; Takata, Tomoaki; Tokonami, Natsuko; Debaix, Huguette; Consolato, Francesco; Rampoldi, Luca; Korstanje, Ron; Devuyst, Olivier

doi:10.1038/s41598-019-48300-3

Cited by 46 publications

(56 citation statements)

References 40 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The expression of uromodulin modulates the activity of NKCC2 and ROMK in the TAL 7,19 , and its deletion in mouse leads to a discrete salt-losing phenotype 35 . We recently showed that defective processing of uromodulin (due to hepsin mutation) is causing TAL dysfunction and salt wasting 36 . All these effects could contribute to the tubular dysfunction typically observed in patients with Bartter syndrome.…”

Section: Discussionmentioning

confidence: 99%

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

Schiano

Glaudemans

Olinger

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Schiano

Glaudemans

Olinger

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In mice, however, hepsin is dispensable for embryonic development, postnatal survival, and liver regeneration (19,20). In addition to the liver, hepsin is expressed, at lower levels, in the kidney and inner ears, where hepsin is implicated in uromodulin processing and auditory nerve development, respectively (21)(22)(23). Moreover, hepsin upregulation has been found in many human cancers, including prostate, kidney, breast, and ovarian cancers (15,24), suggesting a role of hepsin in promoting tumor invasion and metastasis.…”

mentioning

confidence: 99%

Hepsin enhances liver metabolism and inhibits adipocyte browning in mice

Peng

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hepsin is a transmembrane serine protease primarily expressed in the liver. To date, the physiological function of hepsin remains poorly defined. Here we report that hepsin-deficient mice have low levels of blood glucose and lipids and liver glycogen, but increased adipose tissue browning and basal metabolic rates. The phenotype is caused by reduced hepatocyte growth factor activation and impaired Met signaling, resulting in decreased liver glucose and lipid metabolism and enhanced adipocyte browning. Hepsin-deficient mice exhibit marked resistance to high-fat diet-induced obesity, hyperglycemia, and hyperlipidemia. Indb/dbmice, hepsin deficiency ameliorates obesity and diabetes. These data indicate that hepsin is a key regulator in liver metabolism and energy homeostasis, suggesting that hepsin could be a therapeutic target for treating obesity and diabetes.

show abstract

“…It reaches the plasma membrane in a monomeric form. Its luminal release into the urine and subsequent polymerization is dependent on its cleavage mediated by the serine protease hepsin (107). Additionally, small amounts of UMOD are also released basolaterally into the interstitium and blood and show a positive association with kidney function (108).…”

Section: Uromodulinmentioning

confidence: 99%

DAMPs in Unilateral Ureteral Obstruction

Wyczanska

Lange-Sperandio

2020

Front. Immunol.

View full text Add to dashboard Cite

Damage-associated molecular patterns (DAMPs) are released from tubular and interstitial cells in the kidney after unilateral ureteral obstruction (UUO). DAMPs are recognized by pattern recognition receptors (PRRs), which mediate the initiation of an immune response and the release of inflammatory cytokines. The animal model of UUO is used for various purposes. UUO in adult mice serves as a model for accelerated renal fibrosis, which is a hallmark of progressive renal disease. UUO in adult mice enables to study cell death, inflammation, and extracellular matrix deposition in the kidney. Neonatal UUO is a model for congenital obstructive nephropathies. It studies inflammation, apoptosis, and interstitial fibrosis in the neonatal kidney, when nephrogenesis is still ongoing. Following UUO, several DAMPs as well as DAMP receptors are upregulated. In adult UUO, soluble uric acid is upregulated and activates the NOD-like receptor family, pyrin domain containing-3 (NLRP3) inflammasome, which promotes fibrosis, apoptosis, and reactive oxygen species (ROS) injury. Further DAMPs associated with UUO are uromodulin, members of the IL-1 family, and necrotic cell DNA, all of which promote sterile inflammation. In neonatal UUO, the receptor for advanced glycation endproducts (RAGE) is highly upregulated. RAGE is a ligand for several DAMPs, including high mobility group box 1 (HMGB1) and S100 proteins, which play an important role in renal fibrosis. Additionally, necroptosis is an important mechanism of cell death, besides apoptosis, in neonatal UUO. It is highly inflammatory due to release of cytokines and specific DAMPs. The release and recognition of DAMPs initiate sterile inflammation, which makes them good candidates to develop and improve diagnostic and therapeutic strategies in renal fibrosis and congenital obstructive nephropathies.

show abstract

Hepsin-mediated Processing of Uromodulin is Crucial for Salt-sensitivity and Thick Ascending Limb Homeostasis

Cited by 46 publications

References 40 publications

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

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

Hepsin enhances liver metabolism and inhibits adipocyte browning in mice

DAMPs in Unilateral Ureteral Obstruction

Contact Info

Product

Resources

About