Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury

Abstract

Chronic kidney disease (CKD), which is associated with high morbidity, remains a worldwide health concern, while effective therapies remain limited. Hydroxychloroquine (HCQ), which mainly targets toll-like receptor-7 (TLR-7) and TLR-9, is associated with a lower risk of incident CKD. Taking into account that TLR-9 is involved in the development of renal fibrosis and serves as a potential therapy target for CKD, we investigated whether HCQ could attenuate CKD via TLR-9 signal pathway. The effects of HCQ on renal tubulointerstitial fibrosis were further explored using a mouse model of renal tubulointerstitial fibrosis after ischemia/reperfusion injury. Bone marrow-derived macrophages were isolated to explore the effects of HCQ in vitro. Judicious use of HCQ efficiently inhibited the activation of macrophages and MAPK signaling pathways, thereby attenuating renal fibrosis in vivo. In an in vitro model, results showed that HCQ promoted apoptosis of macrophages and inhibited activation of macrophages, especially M2 macrophages, in a dose-dependent manner. Because TLR-7 is not involved in the development of CKD post-injury, a TLR-9 knockout mouse was used to explore the mechanisms of HCQ. The effects of HCQ on renal fibrosis and macrophages decreased after depletion of TLR-9 in vivo and in vitro. Taken together, this study indicated that proper use of HCQ could be a new strategy for anti-fibrotic therapy and that TLR-9 could be a potential therapeutic target for CKD following acute kidney injury.

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

“…In S-100-treated AIH mice, oral administration of 10 or 20 mg/kg HCQ, which referred to the report ( Zheng et al, 2021 ), for 2°weeks markedly diminished the extent of AIH with the loss of liver architecture, congestion, lymphocytic infiltration and large area necrosis (arrows represent inflammatory infiltrations) ( Figure 1A ). We focused on inflammatory cell related markers, such as mature macrophages cell marker F4/80 and lymphocyte marker CD3 to investigate the alleviating effect of HCQ on the inflammatory infiltration of AIH.…”

Hydroxychloroquine Attenuates Acute Inflammation (LPS)-Induced Apoptosis via Inhibiting TRPV1 Channel/ROS Signaling Pathways in Human Monocytes

“…However, the expression of TRPV1, apoptotic, and anti-apoptotic markers was modulated in the cells after treatment with HCQ. Similar to the current results, the protective action of HCQ on the acute INF-induced apoptosis was reported in mice macrophages [50]. In the lymphocytes…”

Evaluation of the Corticosteroid Receptors’ Level in the Kidneys of Rats After Systemic Ischemia-Reperfusion

“…Studies of various scientists have shown that aldosterone, through mineralocorticoid signaling, plays a key role in the pathogenesis of ischemia-reperfusion kidney damage, manifested in the development of progressive renal dysfunction, proteinuria, glomerulosclerosis, tubulointerstitial fibrosis, etc. [2,3,5]. According to Barba-Navarro R. I. blockage of mineralocorticoid receptors with spironolactone before or even after ischemia prevents acute functional and structural damage caused by ischemia-reperfusion [6].…”

“…The kidney is an organ that is very sensitive to hemodynamic disorders and ischemia [3]. Therefore, the study of the reaction of resistance to hypoxia after ischemia-reperfusion disorders is an urgent issue.…”