ABC | Volume 112, Nº5, May 2019

Review Article Amorim et al Kidney disease in diabetes Arq Bras Cardiol. 2019; 112(5):577-587 The generation of RONs occurs in many types of cells in the kidneys and infiltrating cells, such as immune cells, neutrophils and macrophages. A substantial increase in glucose auto-oxidation, combined with greater ETC activation and mitochondrial stress, is accompanied by increased RON production, accounting for nearly 80% of all reactive species. 25,61 In addition to these pathways, other enzymatic systems, such as uncoupled eNOS and NOXs, and non-enzymatic systems, such as Ang II, are involved in ROS generation in the kidney of diabetic patients and obese diabetic patients. 62 The overproduction of RON induced by hyperglycemia reduces the expression of antioxidant enzymes, including the superoxide dismutase (SOD) (particularly the manganese SOD subtype that acts in the mitochondria), thioredoxin reductase, and catalase (CAT), and decreases regeneration of reduced glutathione (GSH) by activation of the polyol pathway. In addition, spontaneous reduction of non-enzymatic antioxidants occurs in consequence of increased ROS in response to increased demand. 63 The SOD is considered the main physiological defense against ROS, as it initiates the enzymatic antioxidant defense by reacting with O2 -• to form H 2 O 2 , which will be degraded by CAT and GPx (Figure 1). 21,59 In low concentrations, RONs modulate transcription factors of antioxidant enzymes, essential for OS attenuation. Among these transcription factors, there is the nuclear erythroid 2-related factor 2 (NRF2), which translocate to the nucleus to activate the transcription of genes responsible for codifying antioxidant enzymes like SOD, CAT and GPx, thereby suppressing the NF-kB activity. However, in ROS overproduction, as found in DM, these defenses are not effective in blocking or preventing the establishment of the redox imbalance. 64 In diabetic kidney, RONs decreases the expression of sirtuins (SIRT), enzymes responsible or modulating the regeneration of antioxidants via acetylation of the ETC, essential for the stimulation of mitochondrial SOD and induction of transcription factors, (such as the PGC1- α ), attenuating mitochondrial stress and NRF2 activation. 62 Also, the O-GlcNAc, product of hexosamines, attenuates the SIRT activity, contributing to exacerbation of this process in DM. 63 In the kidney of diabetic rats, reduced expression of PGC-1 α , a regulator of oxidative metabolism and mitochondrial biogenesis, has been associated with higher production of RONs by aggravating mitochondrial dysfunction and fragmentation. 65 A gradual decrease in the antioxidant defenses in chronic kidney disease has been described in vivo , opening a new field of treatment. 66 Recent studies have shown the efficacy of high antioxidant intake as an adjuvant in the treatment of DKD, by helping in both enzymatic and non-enzymatic antioxidant defense against harmful compounds. 67 In a recent meta-analysis, Bolignano et al. 68 evaluated 14 studies (4,345 participants) for the effects of antioxidant supplementation (including vitamin C, vitamin E and zinc, either combined or alone) on DKD disease progression and markers of renal function. The authors concluded that the antioxidant therapy significantly decreased albuminuria, but apparently had no tangible effect on renal function in patients with diabetic kidney disease. Stronger evidence of benefits was found for vitamin E at doses varying from 480 mg to 1,200 mg/day. Experimental studies on vitamin and mineral supplementation, such as vitamin D, vitamin E and zinc, have shown favorable results in reducing renal failure, inflammation and OS. 67-70 Besides, phenolic compounds and flavonoids have shown beneficial effects as therapeutic agents in the treatment of DKD in cells and animals. 71 Immunological disorders in DKD: the role of inflammation DKD has been associated with systemic and intrarenal inflammation. Persistent metabolic and hemodynamic stimuli in diabetic kidney result in cell lesion that releases molecules known DAMPs – danger-associated molecular pattern – including PGAs, ROS, FFAs. These compounds interact with pattern recognition receptors, including Toll-like receptors 2 and 4 and RAGE, positively regulated by hyperglycemia. In the presence of DAMPs/receptors interaction, the intrarenal innate immune response is activated. 5 The myeloid lineage of innate immune cells causes renal inflammation in diabetic conditions, with involvement of several immune cells in the pathogenesis and severity of renal damage. However, pro-inflammatory factors released in diabetic renal tissue include not only infiltrating inflammatory cells, but also cytokines and chemokines found in non-immune cells, such as in parenchymal cells (podocytes, and endothelial, epithelial, mesangial and tubular cells), exacerbating the inflammatory process that leads to progressive damages in DKD (Chart 1). 19 In addition, the binding of DAMPs with their receptors has been associated with activation of molecular and transcription factors that promote activation of NF- κ B, facilitating the expression of many pro-inflammatory genes (cytokines, chemokines, adhesion molecules, immune receptors and growth factors). Consequently, NF- κ B has been considered a master regulator of immune responses and inflammation in DKD. 26,72 The main proinflammatory cytokines are IL-1, IL-6, IL18 and TNF- α ; all of them have autocrine, paracrine and juxtacrine mechanisms with pleiotropic effects that regulate the expression of cytokines, interleukins, TNF- α , interferons, growth factors, adhesion molecules and nuclear transcription factors, promoting the increase and perpetuation of inflammation and OS in diabetic kidney (Chart 1). 73,74 Intracellular metabolic changes with increased AGEs and ROS lead to increased release of MCP-1, which promotes the activation of monocytes and macrophages. These, in turn, are associated with increased expression of adhesion molecules and synthesis of pro-inflammatory cytokines, leading to hyperfiltration and glomerular lesions, typical of DKD. 75,76 Due to its close relationship with obesity, kidney damage of patients with type 2 DM is associated with early activation of the immune system, which is related to chronic, low-grade systemic inflammation induced by adipose tissue. 44,50 582