SFRP2 aggravates diabetic kidney disease by repressing the renal protective CH25H/25-hydroxycholesterol axis in...

Diabetic kidney disease (DKD) is characterized by renal lipid accumulation, but the molecular mechanisms underlying this lipotoxic phenotype remain unclear. Secreted frizzled-related protein 2 (SFRP2) has been implicated in metabolic regulation, yet its role in renal cholesterol homeostasis and DKD pathogenesis is unknown.

This study aimed to elucidate the function of SFRP2 in regulating cholesterol metabolism in mesangial cells (MCs) and its contribution to DKD progression.

We integrated single-cell transcriptomic data from DKD mouse models with clinical data from DKD patients and functional validation in cells. Mechanistic investigations included intracellular calcium imaging, calcineurin activity assays, immunoprecipitation, chromatin immunoprecipitation, and lipidomic profiling. Therapeutic interventions involved 25-hydroxycholesterol (25-HC) supplementation and sirolimus treatment in DKD models.

SFRP2 expression is significantly elevated in MCs of DKD patients and experimental models, correlating with glomerular cholesterol deposition and renal dysfunction. Mechanistically, SFRP2 triggers intracellular calcium release to activate calcineurin (CN), which dephosphorylates ATF3 and promotes its nuclear translocation. Nuclear ATF3 recruits HDAC1 to epigenetically repress Ch25h expression, reducing 25-HC production. This loss of 25-HC disinhibits SREBP2-driven cholesterol biosynthesis, leading to lipid overload that exacerbates MCs' inflammation and proliferation. Restoration of 25-HC or SREBP2 inhibition with sirolimus effectively ameliorated renal lipidosis and inflammation.

SFRP2 drives renal cholesterol accumulation in DKD through the CN/ATF3/HDAC1/CH25H signaling axis, and therapeutic strategies targeting 25-HC restoration or SREBP2 inhibition show promise for DKD treatment.