Abstract
Despite its critical nature, the role of matrix in calcium oxalate stone formation is poorly understood. The wide diversity of proteins comprising matrix has contributed to the ambiguity. This study compares the protein distributions measured by mass spectrometry in human calcium oxalate stone matrix to that observed in cat stone matrix, because cats share many clinical characteristics of their stone disease with humans. The observed protein distributions were analyzed in the context of a recent model based on the aggregation of strongly anionic and strongly cationic proteins which includes selective adsorption of other proteins based on total charge. Matrix protein distributions shared many common features between species, including enrichment of both strongly anionic and strongly cationic proteins, increased total charge in matrix proteins compared to urine proteins, and a high degree of similarity of prominent strongly anionic proteins in the matrix of both species. However, there was weaker overlap of the specific dominant proteins in other regions of the net charge distribution. Collectively, these observations support the conceptual model where the strongly anionic proteins associate most strongly with the calcium oxalate crystal surfaces, while the other proteins associate with the strongly anionic proteins through non-specific, charge interactions with each other to create stones. Also, cats appear to be the best animal model of human stone disease identified to date based on these similarities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 653-664 |
| Number of pages | 12 |
| Journal | Urolithiasis |
| Volume | 50 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2022 |
Bibliographical note
Funding Information:This study was primarily funded by Department of Veterans Affairs Merit Review (CX-001492, JAW-PI) and in part by a grant from the National Institutes of Health (NIDDK, DK 82550-JAW-PI). Additional financial support was provided by the Froedtert Foundation—Storey Fund and the Medical College of Wisconsin for obtaining earlier human stone matrix data.
Funding Information:
We gratefully acknowledge the support provided with resources and the use of facilities at the Clement J. Zablocki Department of Veterans Affairs Medical Center, Milwaukee, WI throughout this project. We also gratefully acknowledge the technical support from Dr. Neil Mandel, formerly at MIS.MAC (Mandel International Stone and Molecular Analysis Center), Milwaukee, WI, for human stone analysis data, as well as and the technical advice from Akhilesh Pandey, MD, Proteomics Core Facility at the Mayo Clinic. We are also grateful for services provided by the Protein Core Facility at the University of Minnesota, Minneapolis, MN, in generating and providing the mass spectrometry data from cat stone matrix proteins.
Funding Information:
J.W. is the principal investigator for this study and is the principal investigator for both grants. He holds appointments at both the Department of Veterans Affairs Hospital and the Medical College of Wisconsin. He had primary responsibility for directing this research effort and data analysis, and he was primarily responsible for writing this manuscript. R.Z. is a data processing expert and performed all of the primary proteomics analyses, as well as statistical analyses of the data. He generated all Figures in the main manuscript and the Supplementary Data files. He participated in writing and editing the manuscript. He is partially supported by the VA Merit Review grant. J.L. is a veterinarian at the University of Minnesota and had independently acquired stones from some of his feline patients. He also performed protein extractions and arranged for proteomic analysis of those samples at the University of Minnesota Proteomics Core Facility. He subsequently transferred the raw data files to J.W. for data processing and analysis as reported here. He assisted and writing and editing the manuscript, but was not directly funded for this work. J.E. is a Research Associate in Dr Wesson's laboratory and performed protein isolations from urine and human stone samples. She assisted in final editing of the manuscript. She is fully supported the VA Merit Review grant. C.D. is a urologist at the Milwaukee Department of Veterans Affairs Hospital as well as the Academic Affiliate Hospital (Froedtert Hospital) at the Medical College of Wisconsin. She acquired some of the stone samples reported in this manuscript and is a co-Investigator on the VA Merit Review grant. She also assisted in writing and editing this manuscript.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Keywords
- Calcium oxalate
- Kidney calculi
- Nephrolithiasis
- Urine proteome