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Background: Recent clinical studies have shown that proteinuria is a critical factor in the progression of CKD and onset of cardiovascular disease. Inflammation and infiltration of macrophages into renal tissue are implicated as causes of proteinuria. α 1 -Acid glycoprotein (AGP), an acute-phase plasma protein, is leaked into the urine in patients with proteinuria. However, the relationship between urinary leakage of AGP, renal inflammation, and proteinuria remains unclear., Methods: Human AGP (hAGP) was exogenously administrated for 5 consecutive days to adriamycin-induced nephropathy model mice., Results: Adriamycin treatment increased urinary AGP, accompanied by decreased plasma AGP in mice. Exogenous hAGP administration to adriamycin-treated mice suppressed proteinuria, renal histologic injury, and inflammation. hAGP administration increased renal CD163 expression, a marker of anti-inflammatory macrophages. Similar changes were observed in PMA-differentiated THP-1 cells treated with hAGP. Even in the presence of LPS, hAGP treatment increased CD163/IL-10 expression in differentiated THP-1 cells., Conclusions: AGP alleviates proteinuria and renal injury in mice with proteinuric kidney disease via induction of CD163-expressing macrophages with anti-inflammatory function. The results demonstrate that endogenous AGP could work to protect against glomerular disease. Thus, AGP supplementation could be a possible new therapeutic intervention for patients with glomerular disease., Competing Interests: M. Fukagawa reports grants and personal fees from Kyoto Kirin and Ono Pharmaceutical, and personal fees from Bayer Japan. M. Tanaka reports personal fees from Torii and Kyowa Kirin. J. Bi, R. Fujimura, Y. Fujiwara, T. Imafuku, K. Kobayashi, T. Koga, H. Komori, H. Maeda, T. Maruyama, K. Matsushita, M. Miyahisa, K. Nishida, T. Wada, and H. Watanabe have nothing to disclose., (Copyright © 2020 by the American Society of Nephrology.)