Integrins in kidney disease

Abstract

A major hallmark of chronic kidney injury is fibrosis, which is characterized by increased accumulation of extracellular matrix components that replace the damaged tissue. Normally, the synthesis and degradation of extracellular matrix components are finely regulated; however, when matrix replacement goes unchecked, there is unwanted and irreversible tissue scarring with consequent organ damage, organ failure, and, in certain cases, death. Many factors, including cell-matrix interactions, play a role in the development of renal fibrosis. Cell-matrix interactions are made possible by integrins, a family of transmembrane receptors that, upon binding to the extracellular matrix, activate intracellular signaling. Thus, they control various cell functions, including survival, proliferation, migration, and matrix homeostasis. Genetic mutations in humans and the development of animal models lacking integrins in selective parts of the kidney have improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in kidney disease. Here we outline the major integrins involved in kidney disease and some of the major molecular mechanisms whereby integrins contribute to kidney fibrosis.

Figure 1.

Integrin α3β1 is required for podocyte adhesion to the glomerular basement membrane. (A) CD151/integrin α3β1 interactions play an important role in determining strong adhesion of podocytes to the GBM, thus protecting the glomerulus from stress-mediated injury. (B) Loss of CD151 or loss and/or mutations of the integrin α3 subunit leads to podocyte detachment and loss and consequent glomerular damage.

Figure 2.

Collagen binding integrins exert opposing effects in the regulation of glomerular homeostasis. In mesangial cells, integrin α2β1 binding to collagen leads to activation of intracellular signaling (i.e., ERK or Stat3) resulting in increased collagen production. In contrast, activation of integrin α1β1, directly or via negative regulation of integrin α2β1 or epidermal growth factor receptor signaling, leads to reduced production of profibrotic signaling. ROS, reactive oxygen species.

Figure 3.

αv integrins modulates glomerular ECM homeostasis by multiple mechanisms. (A) Schematic representations of mechanisms of activation (i.e., uPAR and suPAR) and inhibition (i.e., integrin α3β1) of integrin αvβ3 in podocytes that contribute to alterations in podocyte cell function. (B) In renal cells (i.e., tubular or mesangial cells), binding of the LAP/TGF-β complex to integrin αvβ6 contributes to release of active TGF-β and increased TGF-β receptor–mediated signaling. In contrast, binding of the LAP/TGF-β complex to integrin αvβ8 sequesters TGF-β, thereby decreasing TGF-β–mediated signaling.