Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease

Om Prakash Dwivedi; Karina Barreiro; Annemari Käräjämäki; Erkka Valo; Anil K Giri; Rashmi B Prasad; Rishi Das Roy; Lena M Thorn; Antti Rannikko; Harry Holthöfer; Kim M Gooding; Steven Sourbron; Denis Delic; Maria F Gomez; iBEAt; Per-Henrik Groop; Tiinamaija Tuomi; Carol Forsblom; Leif Groop; Maija Puhka

doi:10.1016/j.isci.2023.106686

Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease

iScience. 2023 Apr 18;26(5):106686. doi: 10.1016/j.isci.2023.106686. eCollection 2023 May 19.

Authors

Om Prakash Dwivedi¹, Karina Barreiro^{1

2}, Annemari Käräjämäki^{3

4}, Erkka Valo^{5

6

7}, Anil K Giri^{1

8

9

10}, Rashmi B Prasad^{1

11}, Rishi Das Roy¹², Lena M Thorn^{5

6

7}, Antti Rannikko^{13

14}, Harry Holthöfer^{1

15}, Kim M Gooding¹⁶, Steven Sourbron¹⁷, Denis Delic^{18

19}, Maria F Gomez¹¹; iBEAt; Per-Henrik Groop^{5

6

7

20}, Tiinamaija Tuomi^{1

5

11

21}, Carol Forsblom^{1

5

6}, Leif Groop^{1

11}, Maija Puhka^{1

2}

Affiliations

¹ Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
² Institute for Molecular Medicine Finland FIMM, EV and HiPrep Core, University of Helsinki, Helsinki, Finland.
³ Department of Primary Health Care, Vaasa Central Hospital, Hietalahdenkatu 2-4, 65130 Vaasa, Finland.
⁴ Diabetes Center, Vaasa Health Care Center, Sepänkyläntie 14-16, 65100 Vaasa, Finland.
⁵ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
⁶ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁷ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁸ Foundation for the Finnish Cancer Institute (FCI), Tukholmankatu 8, 00290 Helsinki, Finland.
⁹ iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.
¹⁰ HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
¹¹ Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, SE 214 28 Malmö, Sweden.
¹² Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
¹³ Research Program in Systems Oncology, Faculty of Medicine, 00014 University of Helsinki, Helsinki, Finland.
¹⁴ Department of Urology, 00014 University of Helsinki, and Helsinki University Hospital, 00100 Helsinki, Finland.
¹⁵ Department of Medicine, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Diabetes and Vascular Research Centre, National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK.
¹⁷ Department of Imaging, Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
¹⁸ Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
¹⁹ Fifth Department of Medicine, Nephrology/Endocrinology/Rheumatology/Pneumology, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.
²⁰ Department of Diabetes, Central Clinical School Monash University, Melbourne, VIC, Australia.
²¹ Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland.

Abstract

Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB) to construct a transcriptional "stress score" that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.

Keywords: Biopsy sample; Clinical finding; Disease; Medicine; Specimen.