Table 1.
Potential targets for diagnosis and treatment of sepsis-associated AKI found in preclinical studies
| Target | Disease | Model | Intervention | Outcome | Reference |
|---|---|---|---|---|---|
| Microcirculatory dysfunction and pericyte loss | |||||
| Neural glial 2+ pericytes | Nonseptic AKI | Rat, IRI | — | Pericyte density ↓, vascular congestion ↑ | (55) |
| FoxD1+ pericytes | Nonseptic AKI | Mouse, diphtheria toxin | Pericyte ablation | Kidney injury ↑ | (56) |
| Gli1+ pericytes | Nonseptic AKI | Mouse, diphtheria toxin | Pericyte ablation | Kidney injury ↑ | (57) |
| Friend leukemia virus integration 1 | SA-AKI | Mouse, CLP | Inhibition | Vascular leakage ↓, survival ↑ | (58) |
| miR-145a | SA-AKI | Mouse, CLP | Inhibition | Vascular leakage ↑, survival ↓ | (59) |
| PDGFRβ+ pericytes | SA-AKI | Swine, LPS | — | Pericyte-to-myofibroblast transdifferentiation ↑ | (60) |
| NLRP3 inflammasome | |||||
| Sirtuin 3 | SA-AKI | Mouse, LPS | Inhibition | Vascular leakage ↑, survival ↓ | (61) |
| NLRP3 | SA-AKI | Mouse, CLP | Inhibition | Kidney injury ↓ | (69) |
| NLRP3 | Nonseptic AKI | Mouse, cisplatin | Inhibition | Kidney injury → | (70) |
| Panx1 | SA-AKI | Mouse, LPS | Inhibition | Kidney injury ↓ | (71) |
| P2X7 | SA-AKI | Rat, fecal peritonitis | Inhibition | Kidney IL-1β ↓ | (72) |
| miRNAs | |||||
| miR-494 | Nonseptic AKI | Mouse, IRI | Activation | Kidney injury ↑ | (98) |
| miR-452 | SA-AKI | Mouse, LPS, CLP | — | miR-452 ↑ before kidney injury | (92) |
| miR-762, miR-144–3p | SA-AKI | Mouse, LPS | — | miR-762 ↑, miR-144–3p ↑ | (99) |
| miR-34–5b | SA-AKI | Human, LPS-induced HK-2 cells (in vitro) | Inhibition/activation | Inflammation and apoptosis ↓/↑ | (93) |
| Extracellular vesicles | |||||
| Unknown | SA-AKI | Rat, CLP | Brain-derived extracellular vesicles | Kidney injury ↑ | (109) |
| Unknown | Nonseptic AKI | Mouse | Extracellular vesicles secreted on thorax trauma | Kidney injury ↑ | (110) |
| Thioredoxin-interacting protein | SA-AKI | Mouse, CLP | M2 macrophage-derived extracellular vesicles | Kidney injury ↓ | (111) |
| Lysine (K)-specific demethylase 6B | SA-AKI | Mouse, CLP | Endothelial progenitor cell-derived extracellular vesicles | Kidney injury ↓ | (112) |
| Unknown | SA-AKI | Mouse, CLP | Extracellular vesicles from adipose tissue-derived mesenchymal stem cells | Kidney injury ↓ | (113) |
| Autophagy and efferocytosis | |||||
| LC3 | Sepsis | Mouse, LPS | Inhibition | Survival ↓ | (117) |
| LC3 | Sepsis | Mouse, CLP | Activation | Survival ↑, lung injury ↓ | (118) |
| Atg7 | SA-AKI | Mouse, LPS | Inhibition | Kidney injury ↑ | (122) |
| Sirtuin 6 | SA-AKI | Human, LPS-induced HK-2 cells (in vitro) | Activation/inhibition | Inflammation and apoptosis ↓/↑ | (123) |
| p53 | SA-AKI | Mouse, CLP | Deacetylation | Kidney injury ↓ | (124) |
| AIM | Nonseptic AKI | Mouse, IRI | Inhibition/activation | Kidney injury ↑/↓ | (132) |
| Cholinergic anti-inflammatory pathway | |||||
| Vagus nerve | Sepsis | Mouse, LPS | Activation | Plasma TNF-α ↓ | (144) |
| Vagus nerve | Nonseptic AKI | Mouse, IRI | Activation | Kidney injury ↓ | (144,145) |
| Cholinergic anti-inflammatory pathway | Nonseptic AKI | Mouse, IRI | Activation by pulsed ultrasound | Kidney injury ↓ | (146) |
| Cholinergic anti-inflammatory pathway | SA-AKI | Mouse, CLP | Activation by pulsed ultrasound | Kidney injury ↓ | (147) |
| Vitamin D | |||||
| Vitamin D receptor | SA-AKI | Mouse, LPS | Inhibition/activation | Kidney injury ↑/↓ | (153) |
| Vitamin D | SA-AKI | Mouse, LPS | Deprivation | Kidney injury ↑ | (154) |
| Vitamin D receptor | Nonseptic AKI | Mouse, cisplatin | Activation/Inhibition | Kidney injury ↓/↑ | (158) |
| Vitamin D receptor | Nonseptic AKI | Mouse, IRI | Activation | Kidney injury ↓ | (159) |
| Metabolic reprogramming and mitochondrial function | |||||
| PPARγ coactivator-1α | SA-AKI | Mouse, LPS | Inhibition | Kidney injury ↑ | (168) |
| Drp1 | Nonseptic AKI | Mouse, IRI | Inhibition | Kidney injury ↓ | (170) |
| PINK1/PARK2 | SA-AKI | Mouse, LPS, CLP | Inhibition | Kidney injury ↑ | (171) |
| STING | Nonseptic AKI | Mouse, cisplatin | Inhibition | Kidney injury ↓ | (172) |
| cGAS | SA-AKI | Mouse, CLP, LPS | Inhibition | Kidney injury ↓ | (173) |
| Mitochondrial reactive oxygen species | SA-AKI | Mouse, CLP | Antioxidation by SS-31 | Kidney injury ↓ | (174) |
| Drp1 | SA-AKI | Mouse, LPS | Inhibition by Mdivi-1 | Kidney injury ↓ | (76) |
IRI, ischemia-reperfusion injury; FoxD1, forkhead box D1; SA-AKI, sepsis-associated AKI; CLP, cecal ligation puncture; miRNA, microRNA; PDGFRβ, platelet-derived growth factor receptor β; NLRP3, NOD-like receptor protein 3; Panx1, pannexin-1; LC3, microtubule-associated protein 1 light chain 3; Atg7, autophagy-related gene 7; AIM, apoptosis inhibitor of macrophage; Drp1, dynamin-related protein 1; PINK1, PTEN-induced kinase 1; PARK2, Parkin RBR E3 ubiquitin protein ligase; STING, stimulator of interferon genes; cGAS, cyclic GMP-AMP synthase; SS-31, Szeto-Schiller-31.