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Mannan-binding lectin serine protease-2 (MASP-2) in human kidney and its relevance for proteolytic activation of the epithelial sodium channel.
Zachar R
,
Thiel S
,
Hansen S
,
Henriksen ML
,
Skjoedt MO
,
Skjodt K
,
Hamzaei Z
,
Madsen K
,
Lund L
,
Hummler E
,
Svenningsen P
,
Jensen BL
.
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Proteolytic activation of the renal epithelial sodium channel (ENaC) is increased by aldosterone. The aldosterone-sensitive protease remains unidentified. In humans, elevated circulating aldosterone is associated with increased urinary extracellular vesicle (uEVs) excretion of mannan-binding lectin associated serine protease-2 (MASP-2). We hypothesized that MASP-2 is a physiologically relevant ENaC-activating protease. It was confirmed that MASP2 mRNA is abundantly present in liver but not in human and mouse kidneys. Aldosterone-stimulation of murine cortical colleting duct (mCCD) cells did not induce MASP-2 mRNA. In human kidney collecting duct, MASP-2 protein was detected in AQP2-negative/ATP6VB1-positive intercalated cells suggestive of MASP2 protein uptake. Plasma concentration of full-length MASP-2 and the short splice variant MAp19 were not changed in a cross-over intervention study in healthy humans with low (70 mmol/day) versus high (250 mmol/day) Na+ intake despite changes in aldosterone. The ratio of MAp19/MASP-2 in plasma was significantly increased with a high Na+ diet and the ratio correlated with changes in aldosterone and fractional Na+ excretion. MASP-2 was not detected in crude urine or in uEVs. MASP2 activated an amiloride-sensitive current when co-expressed with ENaC in Xenopus oocytes, but not when added to the bath solution. In monolayers of collecting duct M1 cells, MASP2 expression did not increase amiloride-sensitive current and in HEK293 cells, MASP-2 did not affect γENaC cleavage. MASP-2 is neither expressed nor co-localized and co-regulated with ENaC in the human kidney or in urine after low Na+ intake. MASP-2 does not mediate physiological ENaC cleavage in low salt/high aldosterone settings.
OL 8201,ID phd0115 Danish Diabetes Academy, 10-102-00000 Syddansk Universitet, 815 (A) Odense Universitetshospital, 49091 Beckett-Fonden, 95-102-71226 Bagermester August Jensen and wife grants, 21.265 Grosserer L. F. Foghts Fond, 71623 Fru Ruth I.E. Konig-Petersen Reasearch Foundation, 71406 Dansk Nefrologisk Selskab, 31003A_182478/1 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, 31003A_182478/1 Swiss National Science Foundation
Figure 5. Effect of co-expression of MASP-2 and ENaC on current in Xenopus oocytes. (A) When co-injecting cRNAs for αβγENaC and MASP2, an increased amiloride-sensitive current was detected with a concentration of 8 and 12 ng MASP2. (BâD) In Xenopus oocytes injected with cRNAs encoding αβγENaC, no increased amiloride-sensitive current was detected when applying MASP-2 in the buffer, neither when adding the pattern recognition molecule collectin CL-LK (heteromer of collectin liver 1 and kidney 1), known to interact with MASP-2 (C), nor when decreasing the Na+ concentration of the buffer (D).
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