Introduction: 

Ischemia induced acute tubular necrosis (ATN) is one of the main causes of acute kidney injury (AKI). Reperfusion paradoxically increases the injury due to apoptotic processes. MicroRNAs are posttranscriptional regulators of gene-expression. Last year we reported differentially expressed microRNAs (miR-21 and miR-17 family) in renal ischemia-reperfusion (IR) injury. The aim of this study was to further investigate the involvement of the previously identified miRNAs in renal ischemia-reperfusion injury.

Methods: 

We performed lethal (30 min) and sublethal (20 min) unilateral ischemia on the left kidneys of C57BL/6 mice. We then investigated the time-course of (1) microRNA (miR-21 and miR-17) expression (real-time PCR (qPCR)), (2) renal injury markers (a. tubule histopathology, b. renal NGAL (tissue microarray (TMA), qPCR), c. blood urea (Reflotron)), and (3) renal cell proliferation marker (CyclinD1 (TMA)).

Results: 

In lethal ischemia, the time-course analysis revealed that miR-21 and miR-17 expression started to increase only after 24 hours reperfusion (1.7 and 1.9 fold, respectively, p<0.01). Following this time-point the previously significantly diminished (0.4 fold, p<0.01) CyclinD1 proliferation marker started to return to the baseline level.In case of sublethal ischemia, miR-21 and miR-17 levels increased significantly (1.8 fold and 1.6 fold, respectively, p<0.05) together with renal injury markers (urea: 4.7 fold, NGAL mRNA: 37 fold, p<0.001) after 1 day of reperfusion. Renal function was restored on the 4th day of reperfusion. In the mean time miRNA expression level also started to normalize at this late time-point.

Conclusion: 

The miR-21 and miR-17 family timely expression pattern and association with CyclinD1 proliferation marker suggest their involvement in renal tissue regeneration after ischemia-reperfusion injury. As the validated targets of miR-21 and miR-17 are pro-apoptotic proteins (PTEN, PDCD4, and BIM), these miRNAs could inhibit apoptosis during reperfusion and thus, may represent possible therapeutic tools in the treatment of ischemia-reperfusion injury

Support: 

OTKA: K81972, NF69278; ETT: 011-07/2009