WD40 repeat-containing protein 6 aggravates diabetic kidney disease by promoting lipid accumulation in renal tubular cells

ObjectiveTo investigate the role of WD40 repeat domain 6 (WDR6) in the regulation of tubular lipid metabolism in diabetic kidney disease (DKD).MethodsA total of 97 patients who underwent renal biopsy at Linyi People’s Hospital between 2015 and 2023 were selected. Based on pathological diagnoses, they were divided into three groups: non-DKD group (38 cases), DKD stage Ⅱ group (24 cases), and DKD stage Ⅲ group (35 cases). Clinical indicators such as blood lipids, blood glucose, and renal function were measured for all three groups. Renal tissue damage was assessed through renal biopsy pathology. Immunohistochemistry was used to detect the expression of WDR6 and lipid metabolism-related molecules in renal tissue. High-glucose stimulation was applied to human renal tubular epithelial (HK-2) cells, and lipid deposition was observed through oil red O staining. Protein expression and mRNA levels of lipid metabolism-related molecules were analyzed by Western blotting and real-time quantitative PCR. Additionally, the effect of transfecting small interfering RNA to silence WDR6 on the above indicators was observed.ResultsClinical results revealed that compared with the non-DKD group, patients in the DKD groups had lower levels of hemoglobin, estimated glomerular filtration rate (eGFR), total protein, albumin, and globulin, while renal injury markers (urinary protein, urea, serum creatinine) and lipid metabolism-related markers (total cholesterol, low-density lipoprotein cholesterol, alpha-lipoprotein) were significantly elevated (all P<0.05). Pathological examination of renal tissue in DKD groups showed varying degrees of damage. The results of immunohistochemical staining showed that WDR6 is expressed in the human kidney, and the expression of WDR6 and adipose differentiation-related protein (ADRP) in renal tissue was significantly elevated in the DKD groups (both P<0.01). In vitro experiments showed that after 48 hours of high-glucose stimulation, lipid deposition was prominent in HK-2 cells, accompanied by significant increases in the protein and mRNA expression of WDR6, ADRP, sterol regulatory element-binding protein 1 (SREBP1), and fatty acid synthase (FASN) compared with the blank control group (all P<0.01). Silencing of WDR6 significantly reduced high-glucose-induced lipid deposition and the expression of related markers (all P<0.05).ConclusionsWDR6 is expressed in renal tissue, and its elevated levels can affect tubular lipid metabolism, thereby accelerating the pathological progression of DKD.