Molecular Changes in miRNA in Irradiated Rat Kidneys: Role of miR-34a and its Vascular Targets in the Notch Pathway

The mechanism(s) of vascular regression in adult organs remains an unexplored gap. Irradiation to the kidney results in vascular regression and renal failure. The goal of this work was to determine molecular mechanism(s) of radiation-induced vascular regression and its mitigation by the drug lisinopril. Female WAG/RijCmcr rats received either 13 Gy X-ray irradiation, sparing one leg, or no irradiation, the latter serving as age-matched controls. Some irradiated animals received lisinopril. Kidney miRNA-seq was performed 35 days postirradiation, before symptoms of nephropathy. MicroRNA expression profiles were compared with data from humans. MicroRNA targets were predicted using TargetScan and confirmed by qRT-PCR and Western blot. Renal vascular endothelial cell density was evaluated at 100 days to confirm vascular regression. The normal rat kidney microRNA profile resembled that of humans. MiR-34a was increased >7-fold and emerged as the predominant rat microRNA altered by radiation. Expression of Jagged1, a ligand in the Notch pathway of vascular development and a target of miR-34a-5p was decreased by radiation but not in irradiated rats receiving lisinopril. Radiation decreased endothelial cells in the kidneys at 100 days, confirming vascular regression. In conclusion, the results of this study showed that radiation greatly increased miRNA34-a in rat kidneys, while lisinopril mitigated radiation-induced decrease of the Notch ligand, Jagged1, a molecular target of miRNA34-a.