Urinary exosomal transcription factors, a new class of biomarkers for renal disease.
Urinary exosomes are excreted from all nephron segments and constitute a rich source of intracellular kidney injury biomarkers. To study whether they contain transcription factors, we collected urine from two acute kidney injury models (cisplatin or ischemia-reperfusion), two podocyte injury models (puromycin-treated rats or podocin-Vpr transgenic mice) and from patients with focal segmental glomerulosclerosis, acute kidney injury and matched controls. Exosomes were isolated by differential centrifugation and found to contain activating transcription factor 3 (ATF3) and Wilms Tumor 1 (WT-1) proteins detected by Western blot. These factors were found in the concentrated exosomal fraction, but not in whole urine. ATF3 was continuously present in urine exosomes of the rat models following acute injury at times earlier than the increase in serum creatinine. ATF3 was found in exosomes isolated from patients with acute kidney injury but not from patients with chronic kidney disease or controls. Urinary WT-1 was present in animal models before significant glomerular sclerosis and in 9/10 patients with focal segmental glomerulosclerosis but not in 8 controls. Our findings suggest that transcription factor ATF3 may provide a novel renal tubular cell biomarker for acute kidney injury while WT-1 may detect early podocyte injury. Measurement of urinary exosomal transcription factors may offer insight into cellular regulatory pathways.
Renal Diagnostics and Therapeutics Unit, National Institutes of Health, Bethesda, Maryland, USA.
Hua
H
Zhou
Anita
A
Cheruvanky
Xuzhen
X
Hu
Takayuki
T
Matsumoto
Noriyuki
N
Hiramatsu
Monique E
ME
Cho
Alexandra
A
Berger
Asada
A
Leelahavanichkul
Kent
K
Doi
Lakhmir S
LS
Chawla
Gabor G
GG
Illei
Jeffrey B
JB
Kopp
James E
JE
Balow
Howard A
HA
Austin
Peter S T
PS
Yuen
Robert A
RA
Star
D051700:Activating Transcription Factor 3 / Q000652:urine; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000652:urine; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D002945:Cisplatin / Q000633:toxicity; D016336:Gene Products, vpr / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000652:urine; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007668:Kidney / Q000293:injuries; D007674:Kidney Diseases / Q000652:urine*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D050199:Podocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000652:urine; D014157:Transcription Factors / Q000652:urine*; D025721:WT1 Proteins / Q000652:urine
D051700:Activating Transcription Factor 3; D015415:Biomarkers; D016336:Gene Products, vpr; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D014157:Transcription Factors; D025721:WT1 Proteins; D002945:Cisplatin