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Albumin and glycated albumin activate KIM-1 release in tubular epithelial cells through distinct kinetics and mechanisms

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Abstract

Objective

Kidney injury molecule-1 (KIM-1) serves as a useful marker for monitoring tubular injury, and sustained KIM-1 expression may be implicated in chronic kidney fibrosis. In this study, we examine the kinetics and mechanisms of KIM-1 release in human proximal tubular epithelial cells (PTEC) under the activation by major pathologic players in diabetic nephropathy, including human serum albumin (HSA), glycated albumin (AGE-BSA) and high glucose.

Materials and methods

The kinetics of KIM-1 release by PTEC under activation with HSA, AGE-BSA and high glucose, were determined by RT-PCR and ELISA. The activation profiles of major signaling pathways in PTEC were identified by PCR array. Based on the array data, blockade experiments were designed to assess their regulatory roles in KIM-1 release.

Results

Prompt shedding of KIM-1 was observed in PTEC cultured for 4 h with HSA and AGE-BSA, but not with high glucose. Culturing PTEC for 3 days with AGE-BSA exhibited sustained up-regulation of KIM-1 release, but not with HSA. In all culture experiments, high glucose did not induce KIM-1 release in PTEC. HSA and AGE-BSA activated multiple signaling pathways in PTEC including NFκB, ERK1/2 and the oxidative stress pathways. Long-term culturing PTEC with AGE-BSA but not HSA activated the Jak-Stat pathway. While incubation of PTEC with diphenylene iodonium blocked the short-term release of KIM-1 mediated by HSA or AGE-BSA, Jak-Stat inhibitors diminished the long-term KIM-1 release by PTEC induced by AGE-BSA.

Conclusion

KIM-1 release in PTEC was differentially up-regulated by HSA and AGE-BSA. The short-term KIM-1 shedding was mediated by the reactive oxygen species, whereas Jak-Stat pathway regulates the long-term KIM-1 release.

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Acknowledgments

The study was supported by Research Grants from the Hong Kong General Research Fund 772013, Hong Kong Kidney Foundation and Hong Kong Society of Nephrology (2012), and was partly supported by L & T Charitable Foundation and the House of INDOCAFE.

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Authors and Affiliations

  1. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Room 301, Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China

    Ai Ing Lim, Loretta Y. Y. Chan, Sydney C. W. Tang & Joseph C. K. Leung

  2. Nephrology Center, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong, China

    Kar Neng Lai

Authors
  1. Ai Ing Lim
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  2. Loretta Y. Y. Chan
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  3. Sydney C. W. Tang
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  5. Joseph C. K. Leung
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Corresponding author

Correspondence to Joseph C. K. Leung.

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Responsible Editor: Bernhard Gibbs.

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Lim, A.I., Chan, L.Y.Y., Tang, S.C.W. et al. Albumin and glycated albumin activate KIM-1 release in tubular epithelial cells through distinct kinetics and mechanisms. Inflamm. Res. 63, 831–839 (2014). https://doi.org/10.1007/s00011-014-0757-x

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  • DOI: https://doi.org/10.1007/s00011-014-0757-x

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