Indoxyl Sulfate as a Mediator Involved in Dysregulation of Pulmonary Aquaporin-5 in Acute Lung Injury Caused by Acute Kidney Injury

Abstract

High mortality of acute kidney injury (AKI) is associated with acute lung injury (ALI), which is a typical complication of AKI. Although it is suggested that dysregulation of lung salt and water channels following AKI plays a pivotal role in ALI, the mechanism of its dysregulation has not been elucidated. Here, we examined the involvement of a typical oxidative stress-inducing uremic toxin, indoxyl sulfate (IS), in the dysregulation of the pulmonary predominant water channel, aquaporin 5 (AQP-5), in bilateral nephrectomy (BNx)-induced AKI model rats. BNx evoked AKI with the increases in serum creatinine (SCr), blood urea nitrogen (BUN) and serum IS levels and exhibited thickening of interstitial tissue in the lung. Administration of AST-120, clinically-used oral spherical adsorptive carbon beads, resulted in a significant decrease in serum IS level and thickening of interstitial tissue, which was accompanied with the decreases in IS accumulation in various tissues, especially lung. Interestingly, a significant decrease in AQP-5 expression of lung was observed in BNx rats. Moreover, the BNx-induced decrease in pulmonary AQP-5 protein expression was markedly restored by oral administration of AST-120. These results suggest that BNx-induced AKI causes dysregulation of pulmonary AQP-5 expression, in which IS could play a toxico-physiological role as a mediator involved in renopulmonary crosstalk.

Distant organ dysfunction in acute kidney injury

“…37 Recently, a rat model was used to show that indoxyl sulfate, a typical oxidative stress-inducing uraemic toxin, was involved in the dysregulation of pulmonary aquaporin 5 in AKI, whereas the administration of oral spherical adsorptive carbon beads, which lower indoxyl sulfate levels in serum and lung, restores the expression of pulmonary aquaporin 5 protein. 38 Moreover, IL-6 is one of the best described pro-inflammatory mediators of lung injury following AKI, with supporting data from both human studies 39 and mouse models. 32,40 On the other hand, mechanical ventilation may be instrumental for exacerbating end-organ injury in the setting of ventilator-induced lung injury by the translocation of inflammatory mediators (biotrauma) from the lungs into the systemic circulation and likely the activation of proapoptotic pathways.…”

“…26 On the other hand, tubular epithelial cells may directly contribute to the production of inflammatory mediators that may propagate the injury locally or in distant organs. 38 Moreover, IL-6 is one of the best described pro-inflammatory mediators of lung injury following AKI, with supporting data from both human studies 39 and mouse models. 29 The circulation of these inflammatory factors, in turn, may induce remote lung injury.…”

Lung–kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup

“…Correspondingly, it has been shown that ischaemia-reperfusion injury, but not bilateral nephrectomy, leads to changes in lung transcriptome, suggesting that mechanisms other than uraemia alone lead to lung injury [16]. Furthermore, bilateral nephrectomy leads to a significantly decreased expression in the pulmonary predominant water channel, aquaporin 5 (AQP-5), possibly contributing to acute lung injury [20]. Some animal data suggest that the detrimental effects of ischaemia-reperfusion induced AKI on the lung may be averted by IL-6 mediated upregulation of IL-10 production in splenic CD4 + T cells [21].…”

Mitochondria as a Source and a Target for Uremic Toxins

“…Normally, indoxyl sulfate is a substrate for organic anion transporters localized in the basolateral membrane of proximal tubular cells and can be excreted into the urine via active tubular transport [80]. Indoxyl sulfate has a wide toxic effect not only on kidney tubular cells but also on cells from other organs, including muscle, [19] heart [81], brain [82], lung [83,84], and vascular endothelium [85,86]. We believe that one of the main targets of indoxyl sulfate toxicity is the mitochondria, which explains the non-specific toxic nature of the damage it induces in various organs.…”