Targeted protein degradation via nanoparticle-based universal strategy modifies nanoparticles with antibodies and ingeniously utilizes its cellular transport characteristics. This strategy achieved targeted degradation of extracellular proteins without complex design.Image 1.

Objective:To investigate the role of complement C3a receptor in the diabetic nephropathy pathogenesis of db/db mice, and to provide a new target for prevention and treatment of diabetic nephropathy.Methods:Twelve 8-week-old male mice with type 2 diabetes mellitus (db/db mice) and 6 wild-type (db/m) mice were reared in the special pathogen free environment. The mice were grouped into db/m group, db/db group and C3a receptor antagonist group, with 6 mice in each group. db/db model mice were intraperitoneally injected with C3a receptor antagonist (SB290157, 10 mg/kg) once every two days for 8 weeks in C3a receptor antagonist group. Blood and urine samples were collected, and body weight of mice, fasting blood glucose, serum creatinine, blood urea nitrogen, urinary microalbumin/urinary creatinine and urinary N-acetyl-β- D-glucosaminidase (NAG) were detected. Renal tissues were collected, and HE, PAS and Masson stainings were used to observe the pathological changes. Immunohistochemistry, immunofluorescence and Western blotting were used to detect the protein expression levels of C3 and C3a receptor. Western blotting was used to analyze the protein expression levels of kidney injury molecule-1 (Kim-1), α-smooth muscle actin (α-SMA), zonula occluden-1 (ZO-1), vimentin and E-cadherin in renal tissues. Immunofluorescence was used to analyze the protein expression levels and distribution of α-SMA, ZO-1 and Kim-1, and immunohistochemistry was used to analyze the protein expression levels of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). TUNEL assay was used to detect apoptotic cells in renal tissues. Results:Compared with db/m group, body weight, fasting blood glucose, urinary microalbumin/urinary creatinine and urinary NAG in db/db group were significantly higher, while these indicators in C3a receptor antagonist group were slightly lower than those in db/db group (all P<0.01). There were no significant differences in serum creatinine and blood urea nitrogen among the three groups (all P>0.01). Compared with db/m group, db/db group had glomerular hypertrophy, necrosis and exfoliation of renal tubular epithelial cells, and dilation of renal tubules, and C3 and C3a receptor protein expression levels were higher (both P<0.01). Compared with db/db group, C3a receptor antagonist group had less glomerular lesions, mild necrosis of renal tubular epithelial cells and less tubular dilation. Compared with db/m group, the protein expression levels of Kim-1, IL-1 and TNF-α in kidney tissues of db/db group were significantly higher, while Kim-1, IL-1 and TNF-α in C3a receptor antagonist group were significantly lower than those in db/db group (all P<0.01). Compared with db/m group, the protein expression levels of α-SMA and vimentin of renal tubular epithelial cells in db/db group were significantly higher, while the protein expression levels of ZO-1 and E-cadherin were significantly lower (all P<0.01). Compared with db/db group, the protein expression levels of α-SMA and vimentin of renal tubular epithelial cells in C3a receptor antagonist group were significantly lower, and the protein expression levels of ZO-1 and E-cadherin were significantly higher (all P<0.01). Compared with db/m group, the number of apoptotic cells of kidney tissues in db/db group was increased, while the number of apoptotic cells in C3a receptor antagonist group was reduced compared with db/db group. Conclusions:The expression levels of C3 and C3a receptor of kidney tissues in db/db mice are significantly increased. Antagonistic C3a receptor can reduce the body weight, blood glucose, urinary microalbumin/urinary creatinine and urinary NAG, alleviate renal pathological injury, inhibit renal tissue inflammation, apoptosis and renal tubule epithelial-mesenchymal transition in db/db mice.