Urine microRNA as potential biomarkers of autosomal dominant polycystic kidney disease progression: description of miRNA profiles at baseline.
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is clinically heterogenic. Biomarkers are needed to predict prognosis and guide management. We aimed to profile microRNA (miRNA) in ADPKD to gain molecular insight and evaluate biomarker potential.


METHODS
Small-RNA libraries were generated from urine specimens of ADPKD patients (N = 20) and patients with chronic kidney disease of other etiologies (CKD, N = 20). In this report, we describe the miRNA profiles and baseline characteristics. For reference, we also examined the miRNA transcriptome in primary cultures of ADPKD cyst epithelia (N = 10), normal adult tubule (N = 8) and fetal tubule (N = 7) epithelia.


RESULTS
In primary cultures of ADPKD kidney cells, miRNA cistrons mir-143(2) (9.2-fold), let-7i(1) (2.3-fold) and mir-3619(1) (12.1-fold) were significantly elevated compared to normal tubule epithelia, whereas mir-1(4) members (19.7-fold), mir-133b(2) (21.1-fold) and mir-205(1) (3.0-fold) were downregulated (P<0.01). Expression of the dysregulated miRNA in fetal tubule epithelia resembled ADPKD better than normal adult cells, except let-7i, which was lower in fetal cells. In patient biofluid specimens, mir-143(2) members were 2.9-fold higher in urine cells from ADPKD compared to other CKD patients, while expression levels of mir-133b(2) (4.9-fold) and mir-1(4) (4.4-fold) were lower in ADPKD. We also noted increased abundance mir-223(1) (5.6-fold), mir-199a(3) (1.4-fold) and mir-199b(1) (1.8-fold) (P<0.01) in ADPKD urine cells. In ADPKD urine microvesicles, miR-1(2) (7.2-fold) and miR-133a(2) (11.8-fold) were less abundant compared to other CKD patients (P<0.01).


CONCLUSIONS
We found that in ADPKD urine specimens, miRNA previously implicated as kidney tumor suppressors (miR-1 and miR-133), as well as miRNA of presumed inflammatory and fibroblast cell origin (miR-223/miR-199), are dysregulated when compared to other CKD patients. Concordant with findings in the primary tubule epithelial cell model, this suggests roles for dysregulated miRNA in ADPKD pathogenesis and potential use as biomarkers. We intend to assess prognostic potential of miRNA in a followup analysis.
Laboratory of RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, United States of America.
Iddo Z
IZ
Ben-Dov
Molecular Pathology Laboratory, New York Presbyterian Hospital, Cornell University, New York, New York, United States of America ; Pathology and Laboratory Medicine, Weill Medical College, Cornell University, New York, New York, United States of America.
Ying-Cai
YC
Tan
Laboratory of RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, United States of America.
Pavel
P
Morozov
Centre for Nephrology, University College London Medical School, London, United Kingdom.
Patricia D
PD
Wilson
Molecular Pathology Laboratory, New York Presbyterian Hospital, Cornell University, New York, New York, United States of America ; Pathology and Laboratory Medicine, Weill Medical College, Cornell University, New York, New York, United States of America.
Hanna
H
Rennert
Rogosin Institute, Weill Medical College of Cornell University, New York, New York, United States of America.
Jon D
JD
Blumenfeld
Laboratory of RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, United States of America.
Thomas
T
Tuschl
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D005333:Fetus; D015723:Gene Library; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000652:urine; D061251:Primary Cell Culture; D011379:Prognosis; D019459:Urothelium / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; D035683:MicroRNAs