Macrophage Depletion Ameliorates Glycerol-Induced Acute Kidney Injury in Mice

Abstract

Background: This study was conducted to elucidate the role of renal macrophages in the development of acute kidney injury (AKI) in a glycerol (Gly)-induced rhabdomyolysis mouse model. Methods: The experimental model of rhabdomyolysis requires injecting 50% Gly (10 ml/kg) intramuscularly into mice. Control mice were injected into the tail vein with the liposomal vehicle. Liposome-encapsulated clodronate (LEC)-only mice were injected with LEC. Gly-only mice were injected with Gly into a hind limb. LEC+Gly-treated mice were injected intravenously with 100 µl of LEC 24 h prior to Gly injection. Mice were sacrificed 24 h after Gly injection. Results: Gly injection increased the serum creatinine level, and induced tubular damage. Renal CD45⁺CD11b⁺Ly6c⁺ or CD45⁺CD11b⁺Ly6c⁺F4/80⁺ macrophages were decreased by pretreatment with LEC in both normal and injured kidneys. Macrophage depletion prevented Gly-induced apoptotic death of tubular epithelial cells by decreasing caspase-9, ERK and p53, while increasing Bcl-2 expression. Expression of the inflammatory mediators NF-κB, MCP-1, ICAM-1, iNOS and COX-2 were also decreased with LEC pretreatment of mice injected with Gly. Conclusion: These results support the hypothesis that depletion of macrophages prevents renal dysfunction by abrogating apoptosis and attenuating inflammation during AKI.

Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury

“…Moreover, LEC treatment reduced the expression of extracellular matrix molecules such as MMP-2 and MMP-9 in both infiltrating inflammatory and tubular cells. This effect was not attributable to muscular protection because no differences in CPK were observed between groups [24].…”

“…As a result, infiltrated macrophages produce multiple cytokines such as TNF-α, IL-1β, and interferon-γ. Indeed, the number of infiltrated macrophage and pro-inflammatory cytokine levels has been positively correlated with loss of renal function and histologic injury in vivo [24]. It is well known that sterile inflammation triggered by tissue injury can be mediated through multiprotein complexes called the inflammasomes.…”

“…Phagocytes incorporate LEC and undergo apoptosis [71]. Treatment with LEC in a mouse model of rhabdomyolysis led to depletion of infiltrating macrophages, causing preservation of renal function and decreased NF-κβ mediated inflammatory response and production of profibrotic mediators such as TGF-β [24,72]. Moreover, LEC treatment reduced the expression of extracellular matrix molecules such as MMP-2 and MMP-9 in both infiltrating inflammatory and tubular cells.…”

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

“…However, that adaptation resulted in some technical variations, both in the storage media used (10% or 15% glycerol, or D5W alone) and in the strategy of filtration to remove particulate (multistage filtration through a 860 µm and, then, a 190 µm filter, or individual filtrations through 100 µm or 70 µm filters) 13,14,15 . The injection of glycerol alone could potentially cause harm, given that 25%-50% glycerol injections have been used as a rodent model of renal injury 16,17,18,19,20 . To avoid unintended side effects of glycerol, the cecal slurry stock preparation for mice in this study is frozen in D5W without glycerol, and tests of bacterial viability from storage at -80 °C are performed.…”

Efeito da vitamina D na lesão renal aguda provocada por rabdomiólise em ratos

“…D modula ainda diversas citocinas inflamatórias, atenuando a expressão das pró-inflamatórias e aumentando a expressão das anti-inflamatórias(ZHANG et al, 2008). Cantorna (2011) observou em estudos realizados in vitro que o tratamento de células T com calcitriol ou análogos inibe a secreção de Em modelo de nefropatia provocada pela ligadura do ureter, Tan, Li e Liu(2006) observaram que o tratamento com Vit. D, reduzia acentuadamente a fibrose tubulointersticial, inibindo a produção, acúmulo de componentes da matriz e suprimindo a expressão do gene do TGF-β1 (Transforming growth factor-beta 1).…”