Transcriptome analysis supports viral infection and fluoride toxicity as contributors to chronic kidney disease of unknown etiology (CKDu) in Sri Lanka

Abstract

Purpose

Chronic kidney disease of unknown etiology (CKDu), having epidemic characteristics, is being diagnosed increasingly in certain tropical regions of the world, mainly Latin America and Sri Lanka. They have been observed primarily in farming communities and current hypotheses point toward many environmental and occupational triggers. CKDu does not have common etiologies of chronic kidney disease (CKD) such as hypertension, diabetes, or autoimmune disease. We aimed to understand the molecular processes underlying CKDu in Sri Lanka using transcriptome analysis.

Methods

RNA extracted from whole blood was reverse transcribed and used for microarray analysis using the Human HT-12 v.4 array (Illumina). Pathway analysis was carried out using ingenuity pathway analysis (IPA—Qiagen). Microarray results were validated using real-time PCR of five selected genes.

Results

Pathways related to innate immune response, including interferon signaling, inflammasome signaling and TREM1 signaling had the most significant positive activation z scores, where as EIF2 signaling and mTOR signaling had the most significant negative activation z scores. Pathways previously linked to fluoride toxicity; G-protein activation, Cdc42 signaling, Rac signaling and RhoA signaling were activated in CKDu patients. The most significantly activated biological functions were cell death, cell movement and antimicrobial response. Significant toxicological functions were mitochondrial dysfunction, oxidative stress and apoptosis.

Conclusions

Based on the molecular pathway analysis in CKDu patients and review of literature, viral infections and fluoride toxicity appear to be contributing to the molecular mechanisms underlying CKDu.

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Acknowledgements

The authors thank the staff of the Renal Research Centre, District Hospital, Girandurukotte for their support in sample collection.

Funding

The real-time PCR machine used in this study was funded by the National Research Council, Sri Lanka (NRC Grant 11-059).

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Correspondence to Dhammika N. Magana-Arachchi.

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Electronic supplementary material

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Supplementary file 1

. Materials and Methods for Illumina Human HT-12 array. (DOC 52 KB)

Supplementary file 2

. Canonical pathways in CKDu. (PDF 153 KB)

Supplementary file 3

. Diseases and bio functions in CKDu. (PDF 199 KB)

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Sayanthooran, S., Gunerathne, L., Abeysekera, T.D.J. et al. Transcriptome analysis supports viral infection and fluoride toxicity as contributors to chronic kidney disease of unknown etiology (CKDu) in Sri Lanka. Int Urol Nephrol 50, 1667–1677 (2018). https://doi.org/10.1007/s11255-018-1892-z

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Keywords

  • EIF2 signaling
  • Innate immunity
  • Interferon signaling
  • Microarray
  • mTOR signaling
  • RT-qPCR