ABC | Volume 112, Nº5, May 2019

Review Article Amorim et al Kidney disease in diabetes Arq Bras Cardiol. 2019; 112(5):577-587 Chart 1 – Inflammatory cytokines and their effects on renal function in diabetes mellitus Cytokines Stimulated by Specialized producing cells Exerts positive effects on Effects on DKD Target cells in the kidneys Ref. IL-1α, IL-1β Inflammasome IL-18 and NF-κB Macrophages, Granulocytes* ↑ ICAM-1, ↑ VCAM-1, ↑ Prostaglandin E2 ↑ Intraglomerular hemodynamic abnormality, ↑ Synthesis of hyaluronic acid, ↑ Proliferation of mesangial cells and fibroblasts, ↑ECM accumulation Epithelial, Mesangial, Tubular [77, 83] Tubular epithelial Endothelial, Mesangial † Fibroblasts ‡ IL-6 Hyperglycemia, AGEs, TNF-α, LPS, IL-1, IL-4 T lymphocytes, Macrophages, Neutrophils* ↑ MCP-1, ↑ expression of Ang II receptors, ↑ ROS ↑ Recruitment of monocytes, ↑ Differentiation of macrophages, ↑ Synthesis of fibronectin, ↑ Synthesis and accumulation of ECM, ↑ Mesangial cell proliferation, ↑ Endothelial dysfunction ↑ Tubulointerstitial fibrosis Mesangial, Podocytes, Endothelial, Tubular epithelial [84, 85] Endothelial, Podocytes, Mesangial, Tubular epithelial † Fibroblasts ‡ IL-18 NF-κB, Inflammasome, Caspase-1 T lymphocytes and Macrophages* ↑ IFN-γ, ↑ IL-1, IL-6, TNF-α, iNOS, ICAM-1, TGF-β, MCP-1 ↑ Apoptosis of endothelial cells, ↑ infiltration off macrophages and neutrophils Endothelial, Tubular epithelial [30, 86, 87] Epithelial, Tubular † TNF-α NF-κB Dendritic, Monocytes, Macrophages, T lymphocytes* ↑ Immune response ↑ NF-κB ↑ Inflammatory cells, cell infiltration ↑ Citotoxicity, apoptosis, ↑ Endothelial permeability, ↓ Capillary wall barrier function, ↑ PKC, ↑NOX, ↑ ROS; ↑ ECM Mesangial, Podocytes, Endothelial, Glomerular; Tubular epithelial [19, 78, 83] Mesangial, Endothelial, Tubular † *Infiltrating immune cells; † Renal cells; ‡ Other cell types. Ang II: angiotensin 2; ROS: reactive oxygen species; TNF- α : tumor necrosis factors alfa; NF-κB: nuclear factor-kappa B; IFN-γ: interferon gamma; IL-1: interleukin 1; IL-1 α : interleukin 1 alpha; IL-1 β : interleukin 1 beta; IL-6: interleukin 6; IL-18: interleukin 18; IL‑4: interleukin 4; LPS: lipopolysaccharide; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule; ECM: extracellular matrix; NOX: NADPH oxidase; AGE: advanced glycation end-products; MCP-1: monocyte chemoattractant protein; PKC: protein kinase C; iNOS: nitric oxide synthase; TGF- β : transforming growth factor-beta Redox imbalance and inflammation in DKD: a vicious circle Several hemodynamic andmetabolic pathways are involved in the pathogenesis of DKD. In a common pathway, the interrelation between redox imbalance and inflammation induced by hyperglycemia occurs by mechanisms that involves cellular and molecular processes in a cascade of bioenergetic changes, promoting changes in extracellular, cellular and mitochondrial morphology, genetic expressionmodulation, induction of lesions, tissue hypertrophy, and renal fibrosis and necrosis (Figure 3). 74 Inflammation is mediated by the upregulation of NF- κ B expression by OS, AGEs and TNF- α , which controls the immune response by stimulating genetic expression of pro-inflammatory cytokines, adhesion molecules, NOS, cell proliferation and progression of the inflammatory cycle and OS. 77,78 ROS and the AGE-RAGE interaction, stimulated by DM-related hyperglycemia, act as mediators of the multiprotein complex inflammasome Nlrp, which regulates the cleavage of pro-inflammatory cytokines from the mature, active forms into innate immune cells, renal endothelial cells, glomerular cells and podocytes. 79 The upregulation of pro-inflammatory cytokines (IL-1, IL‑6, IL-18, IFN- γ ), mediated by AGE/RAGE, TNF- α and NF- κ B, causes an increase in RONs and transcription factors (Chart 1), which lead to local and systemic inflammation, glomerular and tubular lesions, and ultimately, albuminuria. 80 Among the cytokines, TNF- α is known to cause direct cytotoxicity and apoptosis of renal cells. 17 A recent meta-analysis showed a statistically significant increase in serum concentrations of TNF- α in type 2 DM patients, especially in those with DKD, suggesting that increased inflammatory load in DKD contributes to disease progression. 81 The expression of profibrotic transcription factors, such as the TGF- β and connective tissue growth factor, triggers the recruitment of extracellular matrix-producing cells, accelerating renal sclerotic and fibrotic processes. 9 TGF- β plays pleiotropic effects, promoting hyperplasia and hypertrophy of renal cells. In the extracellular matrix, TGF- β is found in a latent form, bound to proteins, requiring cleavage to release of its free, active form. This activation is performed by mediators produced under hyperglycemic condition, including AGEs, ROS, DAG, PKC, Ang II, among others. Once activated, TGF- β binds to its cell receptor, and regulates the transcription of target genes, including collagen types I, III and IV, fibronectin, plasminogen, and PAI-I, with net effect of protein synthesis and expansion of the extracellular matrix, glomerulosclerosis and renal fibrosis. It also activates NF- κ B, contributing to the production of proinflammatory cytokines, exacerbating local inflammation. 34,74,82 583