Potential Role of Serine Proteases in Modulating Renal Sodium Transport in vivo

Jacquillet, Grégory; Rubera, Isabelle; Unwin, Robert J.

doi:10.1159/000328926

Cited by 7 publications

(8 citation statements)

References 83 publications

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“…We then assessed if AIM might also be cleaved after glomerular filtration, since it is well known that renal tubules express many proteases192021. Of these, we particularly focused on the serine exopeptidases dipeptidyl-peptidase V (DPPIV, also called CD26)222324 and transmembrane protease, serine 2 (TMPRSS2)25, which are apical membrane-bound serine proteases, highly expressing at the brush border of proximal tubular epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

A proteolytic modification of AIM promotes its renal excretion

Yamazaki

Sugisawa

Hiramoto

et al. 2016

Sci Rep

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Apoptosis inhibitor of macrophage (AIM, encoded by cd5l) is a multi-functional circulating protein that has a beneficial role in the regulation of a broad range of diseases, some of which are ameliorated by AIM administration in mice. In blood, AIM is stabilized by association with IgM pentamers and maintains its high circulating levels. The mechanism regulating the excessive accumulation of blood AIM remains unknown, although it is important, since a constitutive increase in AIM levels promotes chronic inflammation. Here we found a physiological AIM-cleavage process that induces destabilization of AIM and its excretion in urine. In blood, IgM-free AIM appeared to be cleaved and reduced in size approximately 10 kDa. Cleaved AIM was unable to bind to IgM and was selectively filtered by the glomerulus, thereby excreted in urine. Amino acid substitution at the cleavage site resulted in no renal excretion of AIM. Interestingly, cleaved AIM retained a comparable potency with full-length AIM in facilitating the clearance of dead cell debris in injured kidney, which is a key response in the recovery of acute kidney injury. Identification of AIM-cleavage and resulting functional modification could be the basis for designing safe and efficient AIM therapy for various diseases.

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Section: Resultsmentioning

confidence: 99%

A proteolytic modification of AIM promotes its renal excretion

Yamazaki

Sugisawa

Hiramoto

et al. 2016

Sci Rep

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“…Secondly, the affinity-purification step was effective but did not fully retrieve all the FP-TAMRA labelled proteins in the sample. Given the ENaC regulators identified, we anticipated the identification of other ENaC regulators, such as furin and prostasin [ 23 ]. Both furin and prostasin were present on the 2D LC-MS/MS compositional analysis, but their active species were not identified with ABPP.…”

Section: Discussionmentioning

confidence: 99%

Proteomic characterization of serine hydrolase activity and composition in normal urine

Navarrete

Krokhin

et al. 2013

Clin Proteom

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BackgroundSerine hydrolases constitute a large enzyme family involved in a diversity of proteolytic and metabolic processes which are essential for many aspects of normal physiology. The roles of serine hydrolases in renal function are largely unknown and monitoring their activity may provide important insights into renal physiology. The goal of this study was to profile urinary serine hydrolases with activity-based protein profiling (ABPP) and to perform an in-depth compositional analysis.MethodsEighteen healthy individuals provided random, mid-stream urine samples. ABPP was performed by reacting urines (n = 18) with a rhodamine-tagged fluorophosphonate probe and visualizing on SDS-PAGE. Active serine hydrolases were isolated with affinity purification and identified on MS-MS. Enzyme activity was confirmed with substrate specific assays. A complementary 2D LC/MS-MS analysis was performed to evaluate the composition of serine hydrolases in urine.ResultsEnzyme activity was closely, but not exclusively, correlated with protein quantity. Affinity purification and MS/MS identified 13 active serine hydrolases. The epithelial sodium channel (ENaC) and calcium channel (TRPV5) regulators, tissue kallikrein and plasmin were identified in active forms, suggesting a potential role in regulating sodium and calcium reabsorption in a healthy human model. Complement C1r subcomponent-like protein, mannan binding lectin serine protease 2 and myeloblastin (proteinase 3) were also identified in active forms. The in-depth compositional analysis identified 62 serine hydrolases in urine independent of activity state.ConclusionsThis study identified luminal regulators of electrolyte homeostasis in an active state in the urine, which suggests tissue kallikrein and plasmin may be functionally relevant in healthy individuals. Additional serine hydrolases were identified in an active form that may contribute to regulating innate immunity of the urinary tract. Finally, the optimized ABPP technique in urine demonstrates its feasibility, reproducibility and potential applicability to profiling urinary enzyme activity in different renal physiological and pathophysiological conditions.

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“…In mammalian kidney, about two-thirds of sodium reabsorption occurs in the proximal tubule, and is achieved mainly by apically-expressed Na + /H + exchangers (NHE). The remaining sodium is reabsorbed by the distal convoluted tubules and the collecting ducts, via Na + -Cl - cotransporters (NCC) and epithelial sodium channels (ENaC), respectively [1]. Hormonal control of sodium reabsorption occurs primarily in the distal convoluted tubules and the collecting ducts [2], suggesting that while NHE performs the majority of sodium reabsorption, this process is fine-tuned by NCC and ENaC in the mammalian kidney.…”

Section: Introductionmentioning

confidence: 99%