## 9 Inhibition of Dendritic Cells Function to Prevent Renal Injury
Specifically, the authors showed that treatment of mice with a novel DCs-suppressant (NK026680) allows a reduction in mortality, suppresses cytokine production (i.e., TNF-\(\alpha\), IFN-\(\gamma\), IL-5, -4, and -2), prevents glomerul nephritis and glomerular damage, and decreases the rates of proteinuria, hematuria, and blood urea nitrogen [26]. The mechanisms explaining NK026680-mediated DCs inhibition have been associated with a decrease in major histocompatibility complex (MHC) class I and II, CD83, and CD86 on human monocyte-derived DCs during immune system stimulation and the inhibition of lymphoproliferative T-cell development. A recent study has revealed both in vitro and in vivo, how overexpression of miR-21 is a self-protective response of the kidney under IR-conditions. Interestingly, this protective role has been explained through the ability of miR-21 to inhibit the maturation of DCs activating PDCD4/NF-kB pathway, with consequent reduction of pro-inflammatory molecules released by DCs 38. Once again, DCs activity has been proven to be crucial in determining the severity of kidney IR-induced damages. Similarly to NAC, Paeonol is a molecule with an anti-oxidant activity. In a murine model of LPS-induced kidney injury, a reduction in blood urea nitrogen and serum creatinine has been observed and it attenuates the effects of LPS on dendritic cells, with significant inhibition of pro-inflammatory cytokines release, and suppression of TLR4 expression and NF-kB signal pathway [54]. Galectin-3 is a surface molecule of DCs crucial in their activation. In animal model it has been observed that its activation protects from cisplatin-induced AKI by promoting TLR-2-dependent activation of IDO1/KYN pathway in renal DCs, resulting in an increased expansion of immunosuppressive Tregs in injured kidneys [55]. Administration of FTY720, a synthetic sphingosine-1-phosphate, attenuated IRI kidney and reduced inflammation. The beneficial effect of FTY720 was associated with the expansion of peripheral CD11b(+) CD11c(+) DC and with maturation of spleen CD11c(+) DC, which showed impaired allostimulatory capacity. Beneficial effects of FTY720 in IRI may be partially mediated by DC modulation or by increasing Treg activity [56]. Overall, all these studies support the idea that manipulation of DCs function may be a promising approach to limit the negative side effects associated with immunological disorders, secondary to ischemic insults or toxic insults [11; 33; 52], and this strategy could be applied to kidney injury, both in native and transplanted kidney. Although these observations are limited to animal models and their application in humans is not so straightforward, directly targeting DCs with therapeutical interventions in AKI seems to be promising. A Possible Role of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) in the Activation of Dendritic Cells  
Matrix metalloproteinases (MMPs) are enzymes able to degrade [57] and remodel extracellular matrix components [58], thus driving cell migration [59; 60]. Their activity is regulated by specific tissue inhibitors, called TIMPs (tissue inhibitors of metalloproteinases) [61]. Monocyte-derived dendritic cells produce active MMPs and TIMPs, and in particular, elevated migratory capability is connected to MMP-9, which can be inhibited by TIMPs [62]. Therefore, MMP/TIMP imbalance plays a central role in the control of inflammatory mechanisms and cell migration, which characterize pathological conditions such as osteoarthritis, atherosclerosis, and cancer. Thus, we can hypothesize a possible effect of MMP/TIMP imbalance in the activation of DC in the setting of acute kidney injury as well. TIMP-2 is a recognized marker of kidney injury, together with IGFBP(insulin growth factor binding protein 7). We can speculate that increased level of TIMP-2 may represent a response of the body to the MMPs activation, in order to reduce DC migration, thus limiting renal injury.