Abstract
BackgroundAutosomal 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.MethodsSmall-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.ResultsIn 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).ConclusionsWe 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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by unpredictable progression rate and incidence of complications
Our broad aim in this study is to examine miRNAs in ADPKD in an attempt to translate methodological advantages of miRNA profiling to the need for biomarkers in assessment of disease progression in ADPKD. miRNAs were profiled from nanogram amounts of input total RNA in clinical biofluid specimens from ADPKD patients and other chronic kidney disease (CKD) patients using deep sequencing of multiplexed small-RNA cDNA libraries
Findings are depicted according to the type of specimen: primary cultures of human kidney cyst-lining or normal tubular epithelia as ex vivo disease model; urine sediment cells; and microvesicles retained following urine centrifugation and ultrafiltration
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by unpredictable progression rate and incidence of complications. Research of potential therapeutics is hampered by lack of short-term surrogate markers of therapeutic effects. Reduction in glomerular filtration rate is a late occurrence in the course of the disease that manifests only after .60% of normal renal parenchyma has sustained permanent damage. Biomarkers of disease progression should reflect short-term changes in rate of cyst development, akin to blood pressure, cholesterol and glycated hemoglobin measurements to predict long-term benefits of respective medications. The prognostic potential of these profiles was not studied [4]. Autosomal dominant polycystic kidney disease (ADPKD) is clinically heterogenic. We aimed to profile microRNA (miRNA) in ADPKD to gain molecular insight and evaluate biomarker potential
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