Involvement of glucocorticoid receptor and peroxisome proliferator activated receptor-γ in pioglitazone mediated chronic gastric ulcer healing in rats

Abstract

Evidences suggest Peroxisome Proliferator Activated Receptor-gamma (PPAR-γ) ligand, pioglitazone results in the attenuation of gastric mucosal injury. But the molecular mechanism through which these agonists actually elicit gastroprotection through modulating inflammatory responses has not yet been established. Chronic gastric ulcer induced in rats by intraluminal application of acetic acid resulted in elevation of proinflammatory cytokines gene expression, such as, TNF-α (Tumor Necrosis Factor-α), IL-1β (Interleukin-1β) and the protein levels of nuclear p65 subunit of NF-κB (Nuclear Factor-κB) but decreased levels of PPAR-γ gene expression. Pioglitazone treatment reduced the severity of ulceration, repressed levels of TNF-α, IL-1β and nuclear p65 subunit as well as increased the abundance of PPAR-γ in gastric mucosa. Moreover, it significantly upregulated protein levels of glucocorticoid receptor demonstrating its possible involvement in pioglitazone mediated ulcer healing along with PPAR-γ. Administration of pioglitazone reverted back the decreased levels of both PPAR-γ and glucocorticoid receptor, resulting in their redistribution to the nucleus from the cytosol in course of ulcer healing. Moreover, pharmacological inhibition of glucocorticoid receptor function by its antagonist (RU486) inhibited pioglitazone mediated downregulation of TNF-α and IL-1β gene expression confirming involvement of glucocorticoid receptor in pioglitazone mediated ulcer healing. Co-immunoprecipitation studies further established association of PPAR-γ with glucocorticoid receptor during ulcer healing which was enhanced following pioglitazone administration. Thus, the present study is first of its kind bearing direct relevance to the participation of both PPAR-γ and glucocorticoid receptor and their physical association in influencing amelioration of inflammatory responses during pioglitazone mediated gastric ulcer healing.