Vacuole Membrane Protein 1 and Acute Response to Renal Ischemia and Ischemia/Reperfusion

Ischemia reperfusion (I/R) injury is an important initiating cause of chronic kidney disease and renal failure. Changes in proximal tubule (PT) morphology, including brush border loss, occur rapidly in response to ischemic stress and I/R injury. Vacuole membrane protein 1 (VMP1) is a compelling target for ischemia-associated renal damage, because it is a necessary regulator of autophagy and the genomic location of hypoxia-responsive microRNA miR-21 lies within an intronic region of the Vmp1 gene. Autophagy is reported to have protective and pathological effects on I/R injury. In this study we find that VMP1 is rapidly upregulated in renal cortex tissue in response to 15 and 30-minutes of ischemia. Intravenous delivery of Vmp1-targeting GapmeR or a scrambled GapmeR was performed on adult male Sprague Dawley rats for two days prior to either 30-minutes of renal ischemia, 30-minutes of ischemia followed by 24-hours of reperfusion (I/R), or corresponding control procedures. Autophagy markers and PT morphology were assessed in the renal cortex. Suppression of ischemia-induced upregulation of VMP1 attenuated PT brush border loss following 30-minutes of ischemia and 24-hours post-I/R. Our study reveals a novel and mechanistically important dissociation between VMP1 expression, miR-21-5p expression, autophagy markers, and I/R tubular injury in the renal cortex.