Inhibition of Gli1 suppressed hyperglycemia-induced meibomian gland dysfunction by promoting pparγ expression.

Diabetes is one of the risk factors for meibomian gland dysfunction (MGD); however, the underlying molecular mechanism remains unknown. The current study aims to examine the effects of glioma-associated oncogene homolog 1 (Gli1), a transcription factor of the sonic hedgehog (Shh) pathway, in the modulation of diabetic-related MGD. Here, using RNA sequencing and qRT-PCR, we examined the mRNA changes of Shh pathway involving genes. mRNA sequencing analysis showed that the Shh pathway involving genes Shh and Gli1 were markedly upregulated in diabetic MG, and qRT-PCR detection of Shh pathway-associated genes found that Gli1 expression increased most significantly. Contrary to the elevation of Gli1 level, the expression of pparγ was downregulated in diabetic MG and in high glucose treated organotypic cultured mouse MG. GANT61, an inhibitor of Gli1, effectively inhibited the reduction of pparγ expression and lipid accumulation induced by high glucose, which was suppressed by pparγ inhibitor T0070907. We further demonstrated that advanced glycation end products (AGEs) treatment also promoted the expression of Gli1 and pparγ in organotypic cultured mouse MG. AGEs inhibitor Aminoguanidine suppressed high glucose caused Gli1 upregulation in organotypic cultured mouse MG. These results suggest that suppression of Gli1 may be a potentially useful therapeutic option for diabetic-related MGD.