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.

Inactivation of Integrin-β1 Prevents the Development of Polycystic Kidney Disease after the Loss of Polycystin-1

“…46 Our findings in a model of ADPKD expand these observations to the collecting ducts, thus strengthening the role of Intb1 in the renal fibrotic process. 47 The reciprocal control of integrins on matrix deposition 48 and ECM on integrin activation makes it difficult to determine whether the upregulation of integrin or ECM comes first.…”

A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules

“…[27][28][29] Global or podocyte-specific deletion of either subunit leads to proteinuria and early death in animals. 28,29,49 Additionally, we and others have recently shown that podocyte injury leads to reduced levels of active b1 in mice and patients, 30,33 which suggests that preventing loss of active b1-integrin levels in podocytes might be protective.…”

“…27 Functional a3b1 is essential for podocyte health and function and maintaining the integrity of podocytes and the glomerular filtration barrier. [28][29][30][31][32][33] PAN treatment also reduces expression of a3b1 in podocytes.…”

Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling

“…Growth factors and cytokines are important regulators of matrix homeostasis (1,2). The cytokine TGF-β is one of the most potent stimulators of fibrosis following chronic injury.…”

“…Integrins are also potent regulators of matrix homeostasis (1,2). They are transmembrane receptors for extracellular matrix components formed by 2 noncovalently associated α and β subunits.…”