αKlotho deficiency in acute kidney injury contributes to lung damage

Abstract

αKlotho is a circulating protein that originates predominantly from the kidney and exerts cytoprotective effects in distant sites. We previously showed in rodents that the lung is particularly vulnerable to αKlotho deficiency. Because acute lung injury is a common and serious complication of acute kidney injury (AKI), we hypothesized that αKlotho deficiency in AKI contributes to lung injury. To test the hypothesis, we created AKI by renal artery ischemia-reperfusion in rats and observed the development of alveolar interstitial edema and increased pulmonary oxidative damage to DNA, protein, and lipids. Administration of αKlotho-containing conditioned media 6 h post-AKI did not alter plasma creatinine but improved recovery of endogenous αKlotho production 3 days post-AKI, reduced lung edema and oxidative damage, and increased endogenous antioxidative capacity in the lung. Intravenously injected αKlotho rapidly exits alveolar capillaries as a macromolecule, suggesting transcytosis and direct access to the epithelium. To explore the epithelial action of αKlotho, we simulated oxidative stress in vitro by adding hydrogen peroxide to cultured A549 lung epithelial cells. Purified recombinant αKlotho directly protected cells at 20 pM with half-maximal effects at 40-50 pM, which is compatible with circulating αKlotho levels. Addition of recombinant αKlotho activated an antioxidant response element reporter and increased the levels of target proteins of the nuclear factor erythroid-derived 2 related factor system. In summary, αKlotho deficiency in AKI contributes to acute lung injury by reducing endogenous antioxidative capacity and increasing oxidative damage in the lung. αKlotho replacement partially reversed these abnormalities and mitigated pulmonary complications in AKI.

The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

“…Nrf2 activation has been identified as a mechanism by which klotho enhances antioxidant defences in neuronal and epithelial cells 16, 17, however, to date the involvement of Nrf2 in klotho‐mediated vascular cell protection has not been investigated.…”

Therapeutic Challenge of Minicircle Vector Encoding Klotho in Animal Model

“…Since Klotho repletion improves multiple renal and extra-renal parameters in both acute and chronic loss of renal function, it is now clear that Klotho deficiency is not a mere biomarker, but pathogenic for renal disease as well [6,24,25]. In this study, we examined whether the Klotho, encoded in MCs, functions properly in Klothodeficiency mouse model of IRI and UUO [26][27][28].…”

Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction

“…4) [3]. In addition, exogenous αKlotho protein protects lung epithelial cells against hydrogen peroxide-induced oxidative damage to DNA, protein and lipid, also via activation of the ARE of target antioxidant proteins in the Nrf2 pathway, in a dose-dependent manner [55]. Thus, the cytoprotective effect of αKlotho on the alveolar epithelium is at least partly mediated via activation of genes that increase endogenous antioxidant capacity [3].…”

“…Acute kidney injury (AKI) [58–62], a common clinical disease, represents a state of heightened oxidative stress [63] and a model of titratable endogenous “pan-αKlotho deficiency” where renal, serum, and urinary αKlotho levels all decrease by up to >90% [15,55,64,65]. Thus, AKI is a useful model for studying the pulmonary complications that develop secondary to systemic organ failure.…”