ERK5, a member of the mitogen activated protein kinase, expressed in the kidneys was smaller (∼80kDa) in apparent molecular mass compared to other organs (∼120kDa). A blocking peptide experiment confirmed that the ∼80kDa detected on Western blots was a specific band detected by the anti-ERK5 antibody. Expression of the known ERK5 variants ERK5a, b, c, and T confirmed that none of the known splice variants encoded for the renal-specific ∼80kDa protein. However, RT-PCR with primers targeting the potential splice sites did not reveal a novel transcript in the kidney. The smaller molecular mass of the kidney-specific ERK5-immunoreactive protein suggested that this cyto-protective molecule may not be fully functional in the kidneys. Lentivirus-mediated in vivo overexpression of full length ERK5 in the mouse kidneys provided protection against renal IR injury. The identity of the renal-specific ∼80kDa ERK5 remains unknown but a better understanding of the ERK5 expression and post-translational processing in the kidneys may reveal a novel strategy for renal protection.