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Urinary miRNA biomarkers of drug-induced kidney injury and their site specificity within the nephron

Brian Chorley, Heidrun Ellinger-Ziegelbauer, Michael Tackett, Frank J. Simutis, Alison H. Harrill, James McDuffie, Elnaz Atabakhsh, Rounak Nassirpour, Laurence O. Whiteley, Jean-François Léonard, Ernie Harpur, Connie L. Chen, Jean-Charles Gautier

Toxicological Sciences (2020) DOI: https://doi.org/10.1093/toxsci/kfaa181
DOI: https://doi.org/10.22427/NTP-DATA-002-00085-0001-0000-6

Publication

Abstract

Drug-induced kidney injury (DIKI) is a major concern in both drug development and clinical practice. There is an unmet need for biomarkers of glomerular damage and more distal renal injury in the loop of Henle and the collecting duct. The Health and Environmental Sciences Institute initiated a cross-laboratory program to identify and characterize urinary MicroRNA (miRNA) patterns reflecting tissue- or pathology-specific DIKI. The overall goal was to propose miRNA biomarker candidates for DIKI that could supplement information provided by protein kidney biomarkers in urine. Rats were treated with nephrotoxicants causing injury to distinct nephron segments: the glomerulus, proximal tubule, loop of Henle, and collecting duct. Meta-analysis identified miR-192-5p as a potential proximal tubule-specific urinary miRNA candidate. This result was supported by data obtained in microdissected nephron segments showing that miR-192-5p expression was enriched in the proximal tubule. Discriminative miRNAs including miR-221-3p and -222-3p were increased in urine from rats treated with loop of Henle versus proximal tubule toxicants in accordance with their expression localization in the kidney. Urinary miR-210-3p increased up to 40-fold upon treatment with loop of Henle toxicants and was also enriched in the distal versus proximal tubule. miR-23a-3p was enriched in the glomerulus and was increased in urine from rats treated with doxorubicin, a glomerular toxicant, but not with toxicants affecting other nephron segments. Taken together these results suggest that urinary miRNA panels with preferential localization in the glomerulus, the proximal and the distal tubules may be useful to discriminate the pathology of drug-induced lesions in the kidney.

Supplemental Materials

Suppl 1. Normalizer Compilation

Suppl 2. Histopathology incidence tables in kidney

Suppl 3. Clinpath and protein biomarkers

Suppl 4. Full list of significantly modulated miRs in individual studies

Suppl 5. Venn lists

Suppl 6. ddPCR_in LCM samples

Suppl 7. sRNAseq in LCM samples

Suppl 8. FirePlex in LCM samples

Suppl 9. Correlation sRNAseq versus FirePlex in LCM samples