HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury

Abstract

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.

Macrophage Phenotype in Kidney Injury and Repair

“…Blockade of the release of high-mobility group box 1 with a glycyrrhizic acid derivative attenuates UUO-mediated kidney injury and fibrosis [32]. Suppressor of cytokine signaling-3 (SOCS-3), an important intracellular negative regulator of several signaling pathways, is found to be highly expressed in renal proximal tubules in response to acute kidney injury.…”

Macrophage polarization in kidney diseases

“…Indeed, our recent studies show a dominance of F4/80+iNOS+ macrophages in kidney interstitium 5 day after UUO injury, indicating a M1 polarization at this stage [13] . Our results are backed by a recent study from a different group showing that the recruited macrophages are mainly M1 macrophages at early stage of UUO.…”

C1q and HMGB1 reciprocally regulate human macrophage polarization

“…10,11 When bound to the Receptor for Advanced Glycation Endproducts (RAGE), it facilitates the transport of RNA and DNA to endosomal TLRs, leading to the production of type 1 interferon (IFN), IFN-inducible genes, and proinflammatory cytokines, which skew the differentiation of monocytes toward proinflammatory macrophages. 9,[12][13][14][15] Significantly elevated serum levels of HMGB1 have been demonstrated in SLE patients, 16,17 and administration of antibodies against HMGB1 confer protection against tissue injury in some experimental models of autoimmune disease and inflammation. 18 HMGB1 has also been shown to suppress inflammation.…”