HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury.
Previous studies have indicated that macrophage phenotype diversity is involved in the progression of renal fibrosis. However, the factors facilitating M1 or M2 phenotypes and the function of these polarized macrophages in kidney injury and fibrosis remain largely unknown. In the present study, we found that macrophages accumulated in the kidney interstitium exhibited mainly as the M1 phenotype at the early stage of unilateral ureter obstruction (UUO). High-mobility group box 1 (HMGB1) protein expressed and released from tubular epithelial cells and interstitial macrophages was essential for the M1 macrophage transition. HMGB1 significantly induced the expression of the M1 marker inducible nitric oxide synthase while decreasing the M2 marker IL-10 in macrophages. Moreover, a glycyrrhizic acid derivative, a blocker of HMGB1 release, reduced UUO-mediated kidney injury and ameliorated UUO-induced renal fibrosis. Interestingly and importantly, UUO caused a low pH value in the urine accumulated in the obstructed ureter, and the acidified urine induced HMGB1 release from tubular epithelial cells and macrophages in vitro. Our data demonstrate that HMGB1 is an essential contributor in facilitating M1 polarization at the early stage of UUO. Inhibition of HMGB1 release may alter macrophage phenotype and contribute to the protection of kidney tissue from injury and fibrosis.
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia; and Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Shaojiang
S
Tian
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia; and.
Lansing
L
Zhang
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia; and Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Junming
J
Tang
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia; and.
Xia
X
Guo
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia; and.
Kun
K
Dong
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia; and Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China sc229@uga.edu.
Shi-You
SY
Chen
D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D019695:Glycyrrhizic Acid / Q000494:pharmacology / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009400:Nephrosclerosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D014517:Ureteral Obstruction / Q000150:complications / Q000276:immunology* / Q000378:metabolism
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D010936:Plant Extracts; D019695:Glycyrrhizic Acid
high-mobility group box 1 protein; macrophage; phenotype; renal fibrosis; unilateral ureter obstruction