title: Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.
abstract: Serum or plasma proteases have been associated with various diseases including cancer, inflammation, or reno-cardiovascular diseases. We aimed to investigate whether the enzymatic activities of serum proteases are associated with the estimated glomerular filtration rate (eGFR) in patients with different stages of chronic kidney disease (CKD). Our study population comprised 268 participants of the "Greifswald Approach to Individualized Medicine" (GANI_MED) cohort. Enzymatic activity of aminopeptidase A, aminopeptidase B, alanyl (membrane) aminopeptidase, insulin-regulated aminopeptidase, puromycin-sensitive aminopeptidase, leucine aminopeptidase 3, prolyl-endopeptidase (PEP), dipeptidyl peptidase 4 (DPP4), angiotensin I-converting enzyme, and angiotensin I-converting enzyme 2 (ACE2) proteases was measured in serum. Linear regression of the respective protease was performed on kidney function adjusted for age and sex. Kidney function was modeled either by the continuous Modification of Diet in Renal Disease (MDRD)-based eGFR or dichotomized by eGFR < 15 mL/min/1.73 m2or <45 mL/min/1.73 m2, respectively. Results with a false discovery rate below 0.05 were deemed statistically significant. Among the 10 proteases investigated, only the activities of ACE2 and DPP4 were correlated with eGFR. Patients with lowest eGFR exhibited highest DPP4 and ACE2 activities. DPP4 and PEP were correlated with age, but all other serum protease activities showed no associations with age or sex. Our data indicate that ACE2 and DPP4 enzymatic activity are associated with the eGFR in patients with CKD. This finding distinguishes ACE2 and DPP4 from other serum peptidases analyzed and clearly indicates that further analyses are warranted to identify the precise role of these serum ectopeptidases in the pathogenesis of CKD and to fully elucidate underlying molecular mechanisms. Impact statement • Renal and cardiac diseases are very common and often occur concomitantly, resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.
authors.affiliation: 1 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wolke
authors.affiliation: 2 Dept. SHIP/KEF, Institute of Community Medicine, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: 3 Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Karlhans
authors.initials: K
authors.lastname: Endlich
authors.affiliation: 3 Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Endlich
authors.affiliation: 4 Institute of Physiology, University Medicine Greifswald, Karlsburg D-17495, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
authors.affiliation: 5 Department of Internal Medicine A, Nephrology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stracke
authors.affiliation: 5 Department of Internal Medicine A, Nephrology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Fiene
authors.affiliation: 5 Department of Internal Medicine A, Nephrology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Aymanns
authors.affiliation: 6 Department of Internal Medicine B, Cardiology, Angiology, Pneumology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.affiliation: 7 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hannemann
authors.affiliation: 1 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald D-17475, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
mesh_terms: D000368:Aged; D000626:Aminopeptidases / Q000097:blood / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D018826:CD13 Antigens / Q000097:blood / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D010122:Cystinyl Aminopeptidase / Q000097:blood / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate; D043384:Glutamyl Aminopeptidase / Q000097:blood / Q000378:metabolism; D006801:Humans; D007931:Leucyl Aminopeptidase / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000097:blood* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism
chemical_list: D003404:Creatinine; D010447:Peptide Hydrolases; D000626:Aminopeptidases; C000593380:LAP3 protein, human; D007931:Leucyl Aminopeptidase; C025579:enkephalin degrading enzyme; D018826:CD13 Antigens; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; C019721:aminopeptidase B; D043384:Glutamyl Aminopeptidase; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
keywords: Protease activity; angiotensin-converting enzyme 2; chronic kidney disease; dipeptidyl-peptidase IV; estimated glomerular filtration rate; renin–angiotensin system