Abstract
Fibrosis is the most common pathophysiological manifestation of Chronic Kidney Disease (CKD). It is defined as excessive deposition of extracellular matrix (ECM) proteins. Embedded within the ECM are a family of proteins called Matricellular Proteins (MCPs), which are typically expressed during chronic pathologies for ECM processing. As such, identifying potential MCPs in the pathological secretome of a damaged kidney could serve as diagnostic/therapeutic targets of fibrosis. Using published RNA-Seq data from two kidney injury mouse models of different etiologies, Folic Acid (FA) and Unilateral Ureteral Obstruction (UUO), we compared and contrasted the expression profile of various members from well-known MCP families during the Acute and Fibrotic injury phases. As a result, we identified common and distinct MCP expression signatures between both injury models. Bioinformatic analysis of their differentially expressed MCP genes revealed similar top annotation clusters from Molecular Function and Biological Process networks, which are those commonly involved in fibrosis. Using kidney lysates from FA- and UUO-injured mice, we selected MCP genes from our candidate list to confirm mRNA expression by Western Blot, which correlated with injury progression. Understanding the expressions of MCPs will provide important insight into the processes of kidney repair, and may validate MCPs as biomarkers and/or therapeutic targets of CKD.
Highlights
The status of the extracellular matrix (ECM) is a major determinant in the regulation of signaling pathways that drive repair
The Matricellular Proteins (MCPs) families Secreted Protein Acidic and Rich in Cysteine (SPARC), CCN, THBS, Small Integrin-Binding Ligand N-linked Glycoprotein (SIBLING) and TN have been well-studied for their important mechanistic roles in repair
We believe that the expression profiles of MCP family members with known function will reflect processes occurring at different stages of kidney repair, and/or fibrosis
Summary
The status of the ECM is a major determinant in the regulation of signaling pathways that drive repair. The diverse activities of MCPs are determined by their multiple functional regions that interact with various ECM and cell surface molecules. Bsp Dmp[1] Dspp Mepe proteins in the cellular environment, MCP expression is tightly regulated and transiently expressed to exhibit context-specific effects during normal tissue remodeling processes (i.e. repair)[4,5]. We confirm the mRNA expression differences of a selection of early and late MCP genes from both mouse models of kidney injury by Western Blot analysis. Our analysis provides new insight into the plasticity of MCP expression throughout the tissue remodeling process in two mechanistically different injury models, and highlights the potential of these injury-specific proteins as diagnostic/prognostic biomarkers and therapeutic targets of fibrosis, for which there is currently no approved treatment
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