The role of cell–extracellular matrix interactions in glomerular injury

Abstract

Glomerulosclerosis is characterized by excessive deposition of extracellular matrix within the glomeruli of the kidney, glomerular cell death, and subsequent loss of functional glomeruli. While in physiological situations the levels of extracellular matrix components are kept constant by a tight balance between formation and degradation, in the case of injury that results in fibrosis there is increased matrix deposition relative to its breakdown. Multiple factors control matrix synthesis and degradation, thus contributing to the development of glomerulosclerosis. This review focuses primarily on the role of cell-matrix interactions, which play a critical role in governing glomerular cell cues in both healthy and diseased kidneys. Cell-extracellular matrix interactions are made possible by various cellular receptors including integrins, discoidin domain receptors, and dystroglycan. Upon binding to a selective extracellular matrix protein, these receptors activate intracellular signaling pathways that can either downregulate or upregulate matrix synthesis and deposition. This, together with the observation that changes in the expression levels of matrix receptors have been documented in glomerular disease, clearly emphasizes the contribution of cell-matrix interactions in glomerular injury. Understanding the molecular mechanisms whereby extracellular matrix receptors regulate matrix homeostasis in the course of glomerular injury is therefore critical for devising more effective therapies to treat and ideally prevent glomerulosclerosis.

Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

“…Deposition of collagen and fibronectin in tissues takes place in inflammatory bowel disease, asthma, scleroderma, lupus nephritis, and glomerulonephritis (11)(12)(13)(14). Significant increases in HA and proteoglycans have been observed in rheumatoid arthritis, inflammatory bowel disease, chronic inflammatory vascular disease, lupus nephritis, Graves ophtalmopathy, and type 1 diabetes (15)(16)(17)(18)(19)(20).…”

Renal-skin syndromes

“…The intracellular region of α6β4 consists in the short tail of α6 and the large β4 cytodomain, which is responsible for the interactions with plectin and collagen XVII in keratinocytes. The ligands of α6 integrin include CD151, collagen XVII and laminin 332. α6β4 not only performs a major adhesive function in cells but also promotes polarization, a final event in epithelial cell differentiation (Borza and Pozzi 2012).…”

Integrins in Kidney Disease

“…No human diseases are directly attributed to mutations in these integrins; however, a large body of evidence suggests that their expression is altered in the course of human kidney disease and that they modulate renal fibrosis in rodents. 20 The first evidence that collagen-binding receptors regulate renal fibrosis comes from studies demonstrating that antiintegrin a1 antibodies reduce scarring in rat models of glomerular injury by inhibiting leukocyte function and the immune response. 21 It was subsequently shown that integrin a1-null mice have decreased glomerular fibrosis in a mouse model of Alport syndrome.…”