Anti-ANGPTL3 antibody and IL-22 fusion protein mitigate nephrotic syndrome via mitochondrial protection, anti-apoptosis, and autophagy suppression.

Backgroud: Nephrotic syndrome (NS) is a major cause of end-stage renal disease. Treating NS relies on immunosuppressants, which have numerous side effects. Therefore, there is an urgent need to identify effective and safe alternative treatments for NS. Angiopoietin-like protein 3 (ANGPTL3) exacerbates proteinuria, whereas interleukin (IL)-22 has a reparative effect on renal cells. Methods: In the present study, we developed a bifunctional anti-ANGPTL3/IL-22 fusion protein and validated its efficacy in an adriamycin-induced nephropathy in mice. Results: The fusion protein significantly decreased the urinary albumin-to-creatinine ratio, serum creatinine, blood urea nitrogen, and total cholesterol levels while increasing serum albumin levels. Pathological renal damage was also alleviated. These therapeutic effects were accompanied by the preservation of mitochondrial integrity, reduced apoptosis, and inhibited autophagy. Finally, we humanized the fusion protein to facilitate its potential clinical translation. Conclusions: In conclusion, our results revealed that the anti-ANGPTL3/IL-22 bifunctional fusion protein ameliorates NS by protecting mitochondria, inhibiting apoptosis, and suppressing autophagy, highlighting a novel therapeutic approach for NS.