N iron ulfurcontaining dehydratase; its activity is sensitive to oxidation [64]. In Conglobatin web kidney diseases, it’s wellknown that oxidative pressure is often a hallmark [65], hence suggesting that aconitase activity is decreased, as reported in CKD induced by cisplatin [47] and 5/6 nephrectomy [66]; too in AKI induced by maleate [67] and I/R [68]. Additionally, as kidney function declines in nephrectomyinduced CKD [61], aconitase activity also decreases [69]. In nondiabetic CKD, isocitrate urinary excretion, aconitase 1 (mitochondrial aconitase), and two (cytosolic aconitase) expression are reduced in kidney tissue [42]. At present, there is certainly no evidence of isocitrate as a signal molecule, and its synthesis appears to be decreased in kidney diseases. On the other hand, itaconate is yet another intermediate of the TCA cycle derived in the decarboxylation of cisaconitate by the immune responsive gene 1 protein (Irg1). Interestingly, itaconate seems to have immunomodulatory effects [70]. Within the I/R model, Irg1 levels boost immediately after 12 h, with a peak at 24 h; the induction of this enzyme on the diverse cell varieties is dependent upon the stimulus. For example, renal cells respond to H2 O2 , increasing Irg1 levels, whereas macrophages respond primarily to proinflammatory stimulus, for instance cytokines and cell lysates, and lesser extent to H2 O2 [71]. Itaconate has protective effects because Irg1 knockout mice exacerbate inflammatory response and decreased survival percentage induced by I/R [71]. Resulting from this immunomodulatory impact, this metabolite has been applied for decreasing damage in kidney tissue and cells. The administration of 4octyl itaconate (OI), a derivate of itaconate with higher fat solubility, by tail vein injection, reduces fibrotic kidney damage induced in UUO or by adenine administration in rats. This effect was partly through the reduction from the canonical signaling of TGF pathway and by recovering antioxidant enzyme expression in adenineinduced kidney damage or decreasing inflammatory response by lowering nuclear factor kappa B (NFB) activation in UUO [72]. In vitro, OI treatment also reduces fibrotic markers fibronectin, plasminogen activator inhibitor 1 (PAI1), and SMA, decreases phosphorylation of p65 subunit of NFB; whereas stimulates antioxidant response via the improve from the nuclear factor erythroid 2related element (Nrf2) and reducing ROS levels in kidney epithelial cells HK2 stimulated with TGF [72]. Dimethyl itaconate (DMI), a different derivate of itaconate, has also been demonstrated to possess a renal protective effect. The treatment of neonatal renal cells with DMI and exposure to hypoxia/reoxygenation (H/R) reduces cell death; furthermore, the antioxidant response is activated as a result of the improve in Nrf2 nuclear translocation [71]. A comparable outcome was demonstrated in macrophages exposed to H/R, in which DMI reduces inflammatory response by decreasing tumor necrosis factoralpha (TNF) and interleukin 1beta (IL1) production via decreasing mitogenactivated protein kinase (MAPK) and NFB activation; this effect was in part on account of the induction of antioxidant response mediated by Nrf2 stimulation [71]. The wellreported mechanism of action of itaconate is by way of its D-4-Hydroxyphenylglycine Protocol binding to Kelchlike ECH associated protein 1 (KEAP1), a damaging regulator of Nrf2, the interaction of itaconate with KEAP1, elicits the dissociation of this final a single from Nrf2, inducing the nuclear translocation of Nrf2 to market antioxidant gene expression [73]. Interestingly, itaconate also.