Piribedil attenuates methotrexate-induced nephrotoxicity in rats: associated changes in miR-205/EGLN2, Nrf2, and PERK/ATF4/CHOP-related stress responses.

Although microRNAs have been investigated, the renoprotective role of microRNA-205 (miR-205) in methotrexate (MTX)-induced nephrotoxicity remains unclear. Accordingly, this study examined changes in miR-205 and its established target EGLN2 in relation to oxidative and endoplasmic reticulum stress responses during piribedil treatment. Rats were randomly divided into four groups (n = 8/group): a normal control group, an MTX group that received a single intraperitoneal injection of methotrexate (20 mg/kg) on day 7, and two piribedil-treated groups that received piribedil orally at 25 or 50 mg/kg/day for 10 consecutive days, with MTX administered on day 7. At the end of the study, blood and kidney samples were collected for biochemical, histopathological, immunohistochemical, and qRT-PCR analyses. MTX induced significant renal impairment, as indicated by increased SCr, BUN, NGAL, and KIM-1, together with marked histopathological alterations. These changes were accompanied by decreased miR-205 and increased EGLN2 expression, alterations in Nrf2-related antioxidant markers, elevated PC levels, and increased PERK/eIF2α/ATF4/CHOP-related ER-stress markers (p < 0.01). In parallel, MTX increased JNK1 and FOS expression, NF-κB p65 immunoreactivity, pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and apoptosis-related markers including caspase-12, caspase-9, and caspase-3 (p < 0.01). Piribedil attenuated renal functional and structural injury, accompanied by reciprocal changes in miR-205/EGLN2 expression and improvement in the investigated antioxidant, ER-stress-, inflammatory-, and apoptosis-related markers. These findings support further evaluation of piribedil as a potential renoprotective agent and indicate that its protective effect in MTX-induced renal injury is accompanied by alterations in miR-205/EGLN2 expression and related cellular stress-response markers.