Vitamin D Receptor Down-Regulation Is Associated With Severity of Albuminuria in Type 2 Diabetes Patients

Context: Inflammation plays an important role in albuminuria in type 2 diabetes mellitus (T2DM). The vitamin D receptor (VDR) has potent anti-inflammatory activities. Objective: To investigate the correlation between VDR expression and albuminuria in T2DM. Design/Setting/Patients: Renal biopsies from T2DM patients with albuminuria (n = 8) and nondiabetic subjects (n = 4) were compared for VDR expression by immunohistochemistry. Recruited T2DM patients (n = 242; estimated glomerular filtration rate > 60 mL/min/1.73 m2) were divided into three groups based on urinary albumin-to-creatinine ratio (uACR): normal albuminuria (uACR < 30 mg/g; n = 85), microalbuminuria (30 mg/g ≤ uACR < 300 mg/g; n = 84), and macroalbuminuria (uACR ≥ 300 mg/g; n = 73), with healthy individuals (n = 72) as controls. Peripheral blood mononuclear cells (PBMCs) from these subjects were analyzed for VDR mRNA (n = 314), TNF-α mRNA (n = 314), microRNA (miR)-346 (n = 120; 30 for each group), and VDR protein (n = 80; 20 for each group). PBMCs from randomly selected subjects (n = 6 for each group) were cultured ex vivo to evaluate the effect of TNF-α on miR-346 and VDR, and miR-346-mediated VDR suppression was further explored in HK2 cells. Results: VDR expression was down-regulated in PBMCs and renal tubular epithelial cells from T2DM patients with albuminuria. VDR mRNA and protein levels were both negatively correlated with uACR, and VDR mRNA was inversely correlated with TNF-α and miR-346 in PBMCs from T2DM patients. TNF-α reduced VDR while inducing miR-346 in cultured PBMCs. TNF-α suppressed VDR by up-regulating miR-346 in HK2 cells. Conclusions: VDR down-regulation in PBMCs is independently associated with the severity of albuminuria in T2DM. TNF-α suppression of VDR in PBMCs and HK2 cells is mediated by miR-346. We identified an correlation between VDR and the severity of albuminuria in type 2 diabetes patients, revealed a novel mechanism of VDR down-regulation via TNF-?-induced up-regulation of miR-346.