ABC | Volume 112, Nº5, May 2019

Review Article Amorim et al Kidney disease in diabetes Arq Bras Cardiol. 2019; 112(5):577-587 dual oxidases 1 and 2 (DUOX1 and DUOX2, respectively). 9 NADPH oxidases are transmembrane proteins responsible for transferring electrons from cytosolic NADPH to the O 2 , which is reduced to O 2 • , thereby perpetuating the oxidative stress state in renal cells. 9,25 NOX-derived ROS regulate physiological processes in the kidneys. However, they are upregulated in hyperglycemic renal cells, and abnormally activated by AGEs, PKC, TGF β and Ang II, resulting in O 2 •- overproduction and accumulation. O 2 •- acts as an important mediator of redox imbalance and damage to different kidney cell components. 9,43 Angiotensin II Chronic hyperglycemia in DM induces increased synthesis of Ang II and its receptors by glomerular and mesangial cells, and podocytes. It increases the expression of renin and angiotensinogen in mesangial cells, elevating intrarenal angiotensin levels. This mechanism is exacerbated by ROS accumulation in adipose tissue, where Ang II is produced. 34,44 Elevations of Ang II contribute to abnormal activation of the renin-angiotensin-aldosterone system (RAAS), aggravating mechanical damages induced by systemic and intraglomerular hypertension in the kidney. Additional effects of Ang II include direct mediation in RON production, early hyperplasia and late hypertrophy of renal cells, by stimulation of TGF- β , IL-6 and MCP-1, and activation and upregulation of NF- κ B. 45 Hemodynamic changes in diabetic kidney damage Early DKD is marked by changes in renal hemodynamics caused by hyperglycemia. 46 The initial hemodynamic events are characterized by glomerular hyperperfusion, hypertension and hyperfiltration, and responsible for functional and structural changes in the glomeruli, resulting in albuminuria, increase followed by decrease of GFR, glomerular hypertrophy, mesangial expansion, podocyte injury, glomerulosclerosis and renal fibrosis, and natural history DKD. 47,48 Hypertension commonly precedes DKD, especially in DM2. However, persistent metabolic disturbances cause sustained hypertension, and dysregulation of pressure levels, inducing and/or aggravating diabetic kidney injury. 45 The mechanism of hypertension in DKD is complex, multifactorial, and involves altered sodium regulation, such as renal tubular reabsorption of sodium, abnormal activation of the RAAS and of sympathetic nervous system (SNS), endothelial cell dysfunction, and increased OS. These processes mediate vasoconstriction and increase extracellular volume with consequent increase in blood pressure. 49,50 Among hemodynamic factors that contribute to hypertension and renal hyperfiltration, RAAS has been the most widely accepted for the development of DKD, and its blockade has shown to delay the progression of the disease. 51 Mechanical stress on vascular wall induced by hypertension, hyperglycemia, inflammation and ROS considerably increase Ang II production in renal cells and contribute to RAAS hyperactivation. 45,51 This in turn, contributes to systemic and renal vascular vasoconstriction, and renal reabsorption of sodium via interaction with Ang II receptor type 1 (AT1) and aldosterone release, leading to elevations in blood pressure, intraglomerular pressure and renal damage. 52 The effects of Ang II on redox imbalance (additional effects of Ang II on inflammation and redox imbalance, and important factors in the pathophysiology of DKD are described above) via production of O2 •- by local NOXs induce endothelial dysfunction (due to an imbalance between vasoconstrictor and vasodilator factors). 53 In response to increased ROS, there is a reduction in the synthesis of NO, a potent vasodilator that interacts with the substrate BH4, reducing eNOS activity. Besides, there is a direct effect of the O2 •- on reducing NO and ONOO - , and reducing NO availability, leading to sustained vasoconstriction. 50 The actions of Ang II, in addition to endothelial dysfunction, vasoconstriction and vascular resistance, induced by the OS, result in elevations in the pressure of afferent arterioles, which, in turn, cause an increase in systemic blood pressure, glomerular hyperperfusion and hyperfiltration, and proteinuria, leading to progressive DKD. 50 In addition, sodium-hydrogen exchangers (NHEs) play an important role on renal and systemic hemodynamics in DKD. NHEs are expressed in different types of renal cells and regulate sodium (Na + ) and hydrogen (H + ) transport, essential for different cell functions, including maintenance of intracellular pH, fluid volume and cell survival. 54 In the kidneys, particularly in tubular cells and macula densa cells, NHE isoforms 1, 2 and 3 (NHE1, NHE2 and NHE3, respectively) play an important role in the pathogenesis of DKD, by inducing intraglomerular hypertension and mesangial proliferation, and by promoting of inhibiting programmed cell death (apoptotic factors), contributing to renal fibrosis. 55 In macula densa cells, the NHE2 receptors are involved in the regulation of renin and salt sensors. The suggested mechanism is that cell shrinkage (induced by hypertonicity), together with Ang II, is the renin-release signal, leading to the overexpression of the RAAS and increase in intraglomerular pressure. This would activate the signaling pathway that results in increased expression of the NHE receptors in renal cells (promoting a vicious circle). 56 Also, salt excess, induced by NHE in the macula densa, causes an increase in intracellular pH and cell depolarization, leading to activation of ROS synthesis by the NOX enzymes. 57 NHEs are targets of many drug therapies, including inhibitors of the RAAS and of SGLTs, which are involved in NHE blockade in the kidneys, contributing to reduction of intraglomerular pressure, and of proliferative and fibrotic processes. 56 Blockade of the RAAS and Ang II with angiotensin- converting enzyme inhibitors and Ang II receptor blockers (either combined or alone), have shown to be effective in reducing proteinuria and delaying the progression of DKD by their hemodynamic/anti-hypertensive, anti-inflammatory and antifibrotic effects, and hence could be used to improve the prognosis of DKD patients. 58 Redox imbalance in DKD OS is the first stage of DKD and activates pathological pathways in practically all types of renal cells, including endothelial, mesangial, epithelial, tubular cells and podocytes. 19 OS results from an imbalance in which the increase in RONs overwhelms the lower efficient (enzymatic and non-enzymatic) antioxidant system, leading to the redox imbalance between pro- and antioxidants. 59,60 581