Table 2.
Specific depletion of myeloid cells and its outcomes in the rodent models of AKI and kidney repair
| Rodent Model(s) | Phase of Injury | Targeting Cell(s) | Depletion Method(s) | Major Finding(s) | Reference |
|---|---|---|---|---|---|
| Cisplatin-induced AKI | Early phase | Neutrophil | Injection (i.p.) of neutralizing Ab (RB6-8C5) against Ly-6G on days −1, 0, +1, and +2 relative to the day of cisplatin injection | Neutrophil depletion insufficiently protects against cisplatin-induced ARF. | (35) |
| Early phase | Macrophage | Injection (i.v.) of liposomal-encapsulated clodronate 2 days before and 1 day after cisplatin injection | Depletion of CD11b+ macrophages insufficiently protects against cisplatin-induced ARF. | (36) | |
| Early phase | Macrophage | Knocking out Cx3cr1 or administration of neutralizing Ab against CX3CR1 either 1 hour or 1 day after cisplatin injection | Blockage of CX3CR1 is insufficient to prevent cisplatin-induced ARF. | (36) | |
| IRI | Early phase | Myeloid phagocytes (circulating monocyte, tissue macrophage, CD11c+ dendritic cell, and neutrophil) | Injection (i.p.) of liposomal-encapsulated clodronate on two successive days before IRI | Depletion of myeloid phagocytes before IRI protects tubular epithelial cells from injury and ameliorates the loss of renal function induced by IRI. | (37,38, 39,40) |
| Early phase | Macrophage | Knocking out Ccr2, Ccl2, or Cx3cr1 | Deletion of Ccr2 and Cx3cr1, but not Ccl2, suppresses macrophage infiltration and protects kidneys from IRI. | (41,42) | |
| Early phase | Macrophage | Injection (i.p.) of neutralizing Ab against CX3CR1 1 hour before IRI | Neutralizing Ab against CX3CR1 partially suppresses macrophage infiltration and protects kidneys from IRI. | (43) | |
| Early phase | Macrophage | Administration (orally) of CCR2 antagonist (RS-504393) every 12 hours from the day of IRI or propagermanium, which targets glycosylphosphatidylinositol-anchored proteins that are closely associated with CCR2, from 8 days before IRI | Both RS-504393 and propagermanium suppress macrophage infiltration and protects against tubular necrosis after IRI. | (42) | |
| Early phase | Macrophage | Knocking out Mif | Deletion of Mif reduces kidney macrophage accumulation in the area of damaged tubules and associated inflammation and protects kidneys from IRI. | (44) | |
| Early phase | Leukocyte | Injection (s.c.) of CXCR4 antagonists, plerixafor (AMD3100) or its monocyclam analogue (AMD3465) 3.5 hours after IRI every 12 hours for 2 days | CXCR4 antagonists suppress CD11b+ (neutrophils and monocytes) and CD4+ lymphocytes 24 hours after IRI, diminish epithelial and endothelial injury and interstitial inflammation, and ameliorate the loss of renal function induced by IRI. | (45) | |
| Adaptive repair phase | Myeloid phagocytes (circulating monocyte, tissue macrophage, CD11c+ dendritic cell, and neutrophil) | Injection (i.p.) of liposomal-encapsulated clodronate on two successive days 2 days after IRI | Depletion of myeloid phagocytes on day 3 after IRI diminishes tubular recovery from IRI, as shown in persistent luminal casts and decreased regenerating tubules. | (37) | |
| Adaptive repair phase | Macrophage | Injection (i.v.) diphtheria toxin to CD11b-DTR allele mice on day 3 and day 5 after IRI | Depletion of macrophages on day 3 and day 5 leads to a striking failure of normal regeneration of kidney tubule epithelium and normal functional recovery of the kidneys. | (46) | |
| Adaptive repair phase | Macrophage and dendritic cell | Injection (i.v.) diphtheria toxin to γ-GT Cre:CSF-1f/f:DTR mice | Proximal tubule–specific depletion of Csf1 decreases reparative macrophage polarization, delays functional and structural recovery, and increases interstitial fibrosis. | (47) | |
| Adaptive repair phase | F4/80+, CD11c+ dendritic cell | Injection (i.v.) of liposomal-encapsulated clodronate on day 1 and day 3 | Depletion of dendritic cells is associated with persistent kidney injury, apoptosis, inflammation, and impaired tubular cell proliferation. | (48) | |
| Maladaptive repair phase | Macrophage | Injection (i.v.) of liposomal-encapsulated clodronate on day 3 every 5 days thereafter until 8 weeks or every 7 days thereafter until 4 weeks after IRI | Depletion of macrophages attenuates interstitial fibrosis, inflammation, and the renal function impairment in the long-term (8 weeks) follow-up after IRI. | (49,50) | |
| Maladaptive repair phase | Macrophage | Knocking out Ccr2 or injection (i.p.) of CCR2 antagonist (RS102895) on day 7 after IRI and every 12 hours for 7 days | Blockage of MCP-1/CCR2 signaling markedly decreases macrophage infiltration and attenuates interstitial fibrosis and sustained inflammation during AKI-to-CKD transition. | (51) | |
| Maladaptive repair phase | Macrophage | Knocking out Il34 | Deletion of Il34 markedly suppresses macrophage proliferation and protects kidneys from AKI and subsequent CKD. | (52) | |
| Proximal tubule injury–mediated by diphtheria toxin in the Ggt1 DTR transgenic mice | Adaptive repair phase | Macrophage and dendritic cell | Injection (i.p.) of liposomal-encapsulated clodronate after DT injection every 3 days or injection of DT in the Ggt1/CD11c DTR double transgenic mice | Depletion of macrophages/dendritic cells induces a striking increase of tubular injury and kidney dysfunction and delays recovery after injury. | (53) |
| Adaptive repair phase | Macrophage and dendritic cell | Knocking out Csf1 or administration of CSF-1R inhibitor (GW2580, an inhibitor of c-fms, via gastric gavage) twice per day | Blocking CSF-1/CSF-1R signaling decreases macrophage/dendritic cell proliferation, markedly inhibits macrophage phenotype transition (from proinflammatory to reparative), and delays recovery from proximal tubule injury. | (53) | |
| Adaptive repair phase | Macrophage and dendritic cell | Injection (i.v.) diphtheria toxin to γ-GT Cre:CSF-1f/f:DTR mice | Proximal tubule–specific depletion of Csf1 decreases reparative macrophage polarization, delays functional and structural recovery, and increases interstitial fibrosis. | (47) | |
| Rhabdomyolysis (intramuscular injection of glycerol)-induced AKI | Early phase and maladaptive repair phase | Macrophage | Injection (i.p.) of liposomal-encapsulated clodronate 1 day before or after the glycerol injection | Depletion of macrophage before rhabdomyolysis improves animal survival and the eGFR at day 2 and subsequently attenuates interstitial fibrosis and inflammation 7 months after rhabdomyolysis. | (54) |
i.p., intraperitoneal; Ab, antibody; ARF, acute renal failure; i.v., intravenous; IRI, ischemic-reperfusion injury; Mif, macrophage migration inhibitory factor; s.c., subcutaneous; DTR, diphtheria toxin receptor; MCP-1, monocyte chemoattractant protein-1; DT, diphtheria toxin.