title: Identification of cathepsin L as a potential sex-specific biomarker for renal damage.
abstract: The renin-angiotensin system is a well-known regulator of blood pressure and plays an important role in the pathogenesis of cardiovascular disease and renal damage. Genetic factors, including single nucleotide polymorphisms and sex, are increasingly recognized as potential risk factors for the development of cardiovascular disease. Double transgenic rats (dTGRs), harboring human renin and angiotensinogen genes, were used in this study to investigate potential sex differences influencing renal function and renal gene expression. dTGR males and females had comparable increases in blood pressure, whereas body weight, albuminuria/proteinuria, and urine flow rate were higher in males. At 8 weeks of age, renal plasma flow and glomerular filtration rate were proportionally lower in males, and renal vascular resistance tended to be higher. Males developed more severe tubulointerstitial and vascular lesions. By the end of week 8, 40%of the males but none of the females had died. Genome expression studies were performed with RNA from kidneys of 7-week-old male and female dTGRs and control rats to further investigate the sex-related differences on a molecular level. Forty-five genes showed sex-dependent expression patterns in dTGRs that were significantly different compared to controls. Cathepsin L, one of the genes differentially expressed between the sexes, was also shown to be strongly associated with the degree of renal injury. In dTGRs, urinary cathepsin L at week 7 was higher in males (nanograms per 24 hours: male, 512±163; female, 132±70). These results reveal a potential new biomarker for the personalized diagnosis and management of chronic kidney disease.
authors.affiliation: Drug Discovery Biology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. yasmina.bauer@actelion.com
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Bauer
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Changbin
authors.initials: C
authors.lastname: Qiu
authors.forename: Axel
authors.initials: A
authors.lastname: Klenk
authors.forename: Bérengère
authors.initials: B
authors.lastname: Renault
authors.forename: Daniel
authors.initials: D
authors.lastname: Wanner
authors.forename: Rolf
authors.initials: R
authors.lastname: Studer
authors.forename: Nina
authors.initials: N
authors.lastname: Killer
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Stalder
authors.forename: Manuel
authors.initials: M
authors.lastname: Stritt
authors.forename: Daniel Stefan
authors.initials: DS
authors.lastname: Strasser
authors.forename: Hervé
authors.initials: H
authors.lastname: Farine
authors.forename: Katalin
authors.initials: K
authors.lastname: Kauser
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
mesh_terms: D000704:Analysis of Variance; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D056668:Cathepsin L / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012079:Renal Circulation / Q000502:physiology; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D046888:Tissue Array Analysis; D014655:Vascular Resistance / Q000502:physiology
chemical_list: D015415:Biomarkers; D000808:Angiotensinogen; D056668:Cathepsin L; D012083:Renin