Characterization of Matricellular Protein Expression Signatures in Mechanistically Diverse Mouse Models of Kidney Injury

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.

Differential Urinary Proteome Analysis for Predicting Prognosis in Type 2 Diabetes Patients with and without Renal Dysfunction

“…In a meta-analysis study of rat glomerular transcriptome profiling, it was confirmed that GM2A was highly expressed in various diabetic kidney disease rat [ 49 ]. Through the mouse kidney injury model experiment, SPARCL1 showed that mRNA expression was not changed in the acute phase, but the expression level was high in the fibrosis of the kidney [ 50 ], and it inhibited the movement and invasion of renal cell carcinoma [ 51 ]. Lastly, ACP 2, one of the lysosomal enzymes, is a protein used in peptiduria [ 52 ] or lysosomal enzymuria [ 53 ] that measures kidney disease in diabetic patients.…”

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

“…Clearly, there is still much to be discovered regarding the exquisite spatiotemporal regulation of MCP expression patterns and functions in the extracellular space during cancer tissue remodeling, similar to the approach taken in fibrosis (17). In this respect, as more and more knowledge accumulates, it should be possible to design appropriate clinical studies that could firmly establish MCPs as useful biomarkers and therapeutic targets in cancer.…”

“…These proteins are primarily implicated in bone morphogenesis and biomineralization, and were thus thought to be exclusively localized to mineralized tissue such as bone and teeth (16). However, apart from these traditional functions, SIBLING members were also shown to influence cellular proliferation/survival pathways, collagen fibrillogenesis, MMP activities and response to injury (17)(18)(19)(20).…”

Osteopontin: The Molecular Bridge between Fat and Cardiac–Renal Disorders

“…As a matricellular protein, OPN is the first mediator associated with ECM degeneration, which stimulates the release of the local fibrogenic mediators and promotes the tissue's failure. In renal inflammation and fibrosis, matricellular OPN is involved in macrophages and T-cell recruitment, contributing to propagate ECM deposition signaling [54,55]. Under chronic renal flow overload, angiotensin II upregulates transforming growth factor β (TGF-β) as well all the mediators associated with ECM turnover, including OPN [14].…”