Acceleration of crescent formation by L1 retrotransposon in mouse BSA-induced nephritis

Abstract

While crescentic glomerulonephritis (GN) is frequently associated with a rapid clinical course and poor prognosis, its pathogenesis has not been elucidated. Bovine serum albumin -induced nephritis (BSA-N), an established mouse model of crescentic GN, is a favorable model for investigation of chronologic gene expression because it is characterized by synchronized progression of crescentic GN. Specific genes expressed in glomeruli of crescentic GN were screened using representational difference analysis before and after crescent formation. The obtained LINE-1 (L1) elements were suppressed and the methylation status of promoter sequences was analyzed. The endogenous reverse transcriptase (RT) of L1 retrotransposon was identified from glomeruli with crescents. L1 retrotransposon was strongly expressed at sites of crescents and tubulo-interstitial areas adjacent to crescents. The marked glomerular crescent formation and renal dysfunction observed in this model significantly reduced on treatment with the non-nucleoside RT inhibitor, efavirenz (EFV) (P<.01). The L1 promoter sequences in mice with crescents were more frequently hypomethylated than those in mice without crescents. Furthermore, the sequences were not affected by EFV treatment. MAPK 13 and c-MYC were strongly expressed in mice with crescents, but their expression decreased on EFV treatment. This study revealed that increased L1 expression in glomeruli of crescentic GN and downregulation of RT activity in L1 decreased crescent formation. Preferential expression of L1 retrotransposon appears to be related to cell proliferative signals. Finally, our findings provide new insights into the epigenetic factors responsible for crescent formation.