Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
OBJECTIVE Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.73 m2 /year, respectively. We used targeted liquid chromatography–tandem mass spectrome-try to measure 38 peptides from 20 proteins implicated in diabetic kidney dis-ease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures. RESULTS The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07–1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product–BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA. CONCLUSIONS Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetes Care |
| Vol/bind | 45 |
| Udgave nummer | 6 |
| Sider (fra-til) | 1416-1427 |
| Antal sider | 12 |
| ISSN | 0149-5992 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Acknowledgments. The authors are grateful for the participation of the study volunteers and for the effort and dedication of all the staff who took part in subject recruitment. Funding. JDRF Network grant 3-SRA-2016-104 (PI:KS) provided major support for this study. The FinnDiane Study was funded by the Folk-h€alsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Liv och H€alsa Society, the Novo Nordisk Foundation (NNF OC0013659), the Helsinki University Hospital Research Funds, and the Academy of Finland (299200, 275614, 316664). The EDC study was funded by National Institutes of Health (NIH) grant DK34818 and the Rossi Memorial Fund. CACTI was funded by NIH grants R01HL113029, R01HL079611, RC1DK086958, and R01DE026480.
Funding Information:
JDRF Network grant 3-SRA-2016-104 (PI:KS) provided major support for this study. The FinnDiane Study was funded by the Folk-häalsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Liv och Häalsa Society, the Novo Nordisk Foundation (NNF OC0013659), the Helsinki University Hospital Research Funds, and the Academy of Finland (299200, 275614, 316664). The EDC study was funded by National Institutes of Health (NIH) grant DK34818 and the Rossi Memorial Fund. CACTI was funded by NIH grants R01HL113029, R01HL079611, RC1DK086958, and R01DE026480. C.P.L. was funded by NIDDK grants T32DK007467 and R01DK088762 and Northwest Kidney Cen-ters. R.G.N. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the imaging of kidney tissue specimens was also supported in part by the American Diabetes Association (Clinical Science Award 1-08-42). L.N. and J.Z. were partially supported by NIDDK grant 1R01DK110541-01A1. The development of the urine proteomics assay was partially supported by the University of Washington Nutrition Obesity Research Center (P30 DK035816) and Diabetes Research Center (P30 DK017047). This study was also supported, in part, by the George M. O’Brien Michigan Kidney Translational Core Center, funded by NIH/ NIDDK grant 2P30-DK-081943. The KPMP is funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937. I.H.d.B. has obtained research funding from the NIH and the American Diabetes Association. S.E.R. reports grants through the Joslin Diabetes Center with NIDDK. M.K. reports grants outside the sub-mitted work through the University of Michigan with NIH and JDRF.
Funding Information:
Center with Bayer and AstraZeneca. M.K. reports grants and contracts outside the submitted work through the University of Michigan with Chan Zuckerberg Initiative, AstraZeneca, Novo Nordisk, Eli Lilly, Gilead, Goldfinch Bio, Janssen, Boehringer Ingelheim, Moderna, European Union Innovative Medicine Initiative, Certa, Chinook, amfAR, Angion, Renalytix, Tra-vere Therapeutics, Regeneron Pharmaceuticals, and IONIS and consulting fees through the University of Michigan from Astellas Pharma, Poxel, Janssen, and UCB. Additionally, M.K., W.J., and V.N. have a patent, PCT/EP2014/073413 “Biomarkers and methods for progression prediction for chronic kidney disease,” licensed. No other potential conflicts of interest relevant to this article were reported. Author Contributions. C.P.L. drafted the manuscript. E.V. conducted statistical analyses for the primary cohort study. C.P.L., V.D., D.M., W.J., V.N., and S.A. additionally conducted secondary statistical and bioinformatics analyses. V.D. led mouse and cell culture studies. A.N.H., K.S., and I.H.d.B. serve as primary investigators for this proteomics project and obtained funding. C.F. and N.S. contributed to the study design. T.S.A. participated in data management and cleaning. P.R., P.-H.G., J.K.S.-B., T.C., and T.J.O. serve as primary investigators of the four studied cohorts and obtained funding. S.S.W. serves as primary investigator for the BKBC. R.G.N. serves as primary investigator for the Pima Indian cohort, and M.K. serves as the principal investigator for the Pima cohort tran-scriptome data analysis. J.F.O., R.D.T., S.E.R., and S.S.W. serve as heads of KPMP recruitment sites. A.N.H., K.S., and I.H.d.B. supervised the project. All authors contributed to interpretation of results and read, edited, and approved the final manuscript. C.P.L. and E.V. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the American Society of Nephrology's Kidney Week 2020, Denver, CO, 20–25 October 2020.
Funding Information:
C.P.L. was funded by NIDDK grants T32DK007467 and R01DK088762 and Northwest Kidney Centers. R.G.N. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the imaging of kidney tissue specimens was also supported in part by the American Diabetes Association (Clinical Science Award 1-08-42). L.N. and J.Z. were partially supported by NIDDK grant 1R01DK110541-01A1. The development of the urine proteomics assay was partially supported by the University of Washington Nutrition Obesity Research Center (P30 DK035816) and Diabetes Research Center (P30 DK017047). This study was also supported, in part, by the George M. O’Brien Michigan Kidney Translational Core Center, funded by NIH/ NIDDK grant 2P30-DK-081943. The KPMP is funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937. I.H.d.B. has obtained research funding from the NIH and the American Diabetes Association. S.E.R. reports grants through the Joslin Diabetes Center with NIDDK. M.K. reports grants outside the submitted work through the University of Michigan with NIH and JDRF. Duality of Interest. I.H.d.B. has received equipment and supplies for research from Medtronic and Abbott and consults for Boehringer Ingelheim and Ironwood. P.-H.G. has received investigator research grants from Eli Lilly and Roche and lecture honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, and Sanofi. P.-H.G. is an advisor for AbbVie, Astra-Zeneca, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, MSD, Novartis, Novo Nordisk, and Sanofi. P.R. has received consultancy and/or speaking fees (to his institution) from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead Sciences, Novo Nordisk, Vifor Pharma, and Sanofi and research grants from AstraZeneca and Novo Nordisk. K.S. is on the advisory board for Boehringer Ingelheim and Janssen and has received research support from Merck and Boehringer Ingelheim. S.E.R. reports grants and contracts through the Joslin Diabetes
Publisher Copyright:
© 2022 by the American Diabetes Association.
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210873/pdf/dc212204.pdf
Forlagets udgivne version
ID: 313875709