The role of nitric oxide in sepsis-associated kidney injury

Abstract

Sepsis is one of the leading causes of acute kidney injury (AKI), and several mechanisms including microcirculatory alterations, oxidative stress, and endothelial cell dysfunction are involved. Nitric oxide (NO) is one of the common elements to all these mechanisms. Although all three nitric oxide synthase (NOS) isoforms are constitutively expressed within the kidneys, they contribute in different ways to the nitrergic signaling. While the endothelial (eNOS) and neuronal (nNOS) isoforms are likely to be the main sources of NO under basal conditions and participates in the regulation of renal hemodynamics, the inducible isoform (iNOS) is dramatically increased in conditions such as sepsis. The overexpression of iNOS in the renal cortex causes a shunting of blood to this region, with consequent medullary ischemia in sepsis. Differences in the vascular reactivity among different vascular beds may also help to explain renal failure in this condition. While most of the vessels present vasoplegia and do not respond to vasoconstrictors, renal microcirculation behaves differently from nonrenal vascular beds, displaying similar constrictor responses in control and septic conditions. The selective inhibition of iNOS, without affecting other isoforms, has been described as the ideal scenario. However, iNOS is also constitutively expressed in the kidneys and the NO produced by this isoform is important for the immune defense. In this sense, instead of a direct iNOS inhibition, targeting the NO effectors such as guanylyl cyclase, potassium channels, peroxynitrite, and S-nitrosothiols, may be a more interesting approach in sepsis-AKI and further investigation is warranted.

Hypoxia-Driven Responses in Chronic Kidney Disease

“…The kidney is particularly susceptible to damage from oxidative stress because of its high levels of oxidation inside the mitochondria [76]. The substantial immunological response that occurs in sepsis-induced AKI promotes the activation of inducible NOS synthase and the overproduction of NO, which leads to endothelial damage, localized hypoxia and ROS [77]. Cisplatin-induced AKI is characterized by the generation of mitochondrial ROS (mtROS), reduced mitochondrial membrane potential and mitochondrial swelling [78].…”

Chronodisruption of the acute inflammatory response by night lighting in rats

“…Increased daytime transcription of these genes agrees with our previous study and confirms disturbed renal homeostasis due to dim ALAN exposure 14 . Endothelial NOS contributes significantly to NO production in the kidney, playing an important role in the control of renal perfusion 44 . Moreover, NO generated by eNOS has been shown to regulate mitochondrial biogenesis through cGMP-dependent activation of Pgc-1α expression 45 .…”

Acute Kidney Injury in Sepsis

“…Previously, it was believed that the primary driver of the initial injury in SA-AKI was related to the macrocirculatory abnormalities that occur in sepsis, secondary to a demand and perfusion mismatch. Heightened cytokine-induced nitric oxide synthesis leads to generalized arterial vasodilation and decreased systemic vascular resistance, increasing the risk of impaired organ perfusion in the setting of an increased metabolic demand [8,10,15,16]. However, it appears that many more concurrent factors are implicated.…”