Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: <i>In Vivo</i> and <i>in Silico</i> Studies

Abstract

Glomerulonephritis (GN) is a set of pathological conditions that result in the destruction of glomeruli and loss of renal function, commonly leading to the development of end-stage renal disease. Current pharmacotherapy is limited to immunosuppressive therapy. In the present study, we found a novel antinephritic effect of a tricaprylin emulsion in the anti-glomerular basement membrane (anti-GBM) GN rat model. We evaluated the treatment in vivo by comparing administration of the emulsion with administration of a casein kinase II (CK2) inhibitor in this rat model, and performed a gene ontology-based microarray analysis to reveal in silico the detailed mechanism of action. Our results showed that administration of the tricaprylin emulsion, or even tricaprylin alone, significantly ameliorated the anti-GBM antibody-induced renal dysfunction in these rats. We believe that tricaprylin is the key active antinephritic component of the emulsion and might be a promising drug for the effective treatment of nephritis. Moreover, with respect to microarray analysis, we developed a generally applicable and rapid method to compare gene expression profile data for multiple models of nephritis and clinical samples from a public domain microarray database.Key words tricaprylin; crescentic glomerulonephritis; microarray; gene ontology Glomerulonephritis (GN) is a progressive inflammation of the glomeruli that can be caused by a variety of underlying disorders. It is one of the primary causes of renal failure and end-stage renal disease that require dialysis and transplantation. Immunosuppressive therapy has been used to treat GN clinically, but the therapeutic benefits of this treatment are limited and the treatment per se can also cause renal damage. 1)Crescentic GN is also called rapidly progressive GN; if left untreated, it rapidly progresses into acute renal failure. Anti-glomerular basement membrane (anti-GBM) GN is a typical type of crescentic GN. It is characterized clinically by the rapid deterioration of renal function and histologically by mononuclear cell infiltration into the stroma, glomerular cell proliferation, crescent formation in the glomerulus with the deposition of anti-GBM antibodies.2) To investigate this disease, we utilized an experimental model in Wistar-Kyoto (WKY) rats, in which injection of rabbit anti-rat GBM antiserum induces severe proliferative and necrotizing GN with crescent formation that resembles human anti-GBM GN. 3)Previously, we identified the protein kinase casein kinase II (CK2) as a GN-related gene through microarray analysis performed on these anti-GBM GN model rats, and demonstrated that in vivo inhibition of the kinase ameliorates renal dysfunction and histological progression of the condition.2) Furthermore, previous studies using the same model of anti-GBM GN have suggested that several genes are also relevant to the onset of anti-GBM GN. 4)The study reported herein shows a novel antinephritic effect observed in the anti-GBM GN rat model following administration of an emulsion containi...

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