Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Abstract

Mesangial cells and podocytes express integrins a1b1 and a2b1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin a1b1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin a2b1 in renal injury is unclear. Here, we subjected wild-type and integrin a2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin a2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin a2b1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wildtype mice. This inhibitor significantly reduced collagen synthesis in wild-type, but not integrin a2-null, mesangial cells in vitro, demonstrating that its effects are integrin a2b1-dependent. Taken together, these results indicate that integrin a2b1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria. The most common cause of end stage kidney disease is glomerulosclerosis, which is characterized by excessive collagen deposition in the glomerulus. Although numerous disease processes can initiate glomerular injury, they all result in abnormal glomerular collagen homeostasis with progression. Glomerular collagen turnover is regulated by multiple factors, including growth factors and profibrotic reactive oxygen species (ROSs) as well as cell extracellular matrix interactions mediated by the matrix receptors integrins (reviewed in ref. 1). Of these factors, the mechanisms by which integrins regulate glomerulosclerosis are the most poorly understood.Integrins consist of two noncovalently associated a-and b-subunits that combine to form 24 different heterodimers in mammals (reviewed in ref.2). The integrin extracellular domains contain the ligand binding site and confer ligand specificity, whereas the cytoplasmic domain interacts with the cytoskeleton and regulates cell signaling. Integrins control critical cell functions, including proliferation, survival, migration, and matrix homeostasis (reviewed in refs. 1 and 2). Thus, it is not surprising that integrins regulate tissue responses to injury in whole organisms.The best-studied integrin in the context of glomerular injury is the major collagen IV receptor, integrin a1b1, which is expressed by mesangial cells 3 and podocytes. 4 We have shown that integrin

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

“…45 Recently, Inta2/b1 was shown to exert a deleterious effect in glomerular injury by upregulating collagen production. 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.…”

The integrin–collagen connection – a glue for tissue repair?

“…In a more recent study, reduced pathological neovascularization in integrin α2 −/− mice was observed in a model for retinopathy (Madamanchi et al, 2014a). The absence of α2 is known to delay fibrosis and glomerular damage in experimental kidney disease models, including the Alport syndrome mouse model (Borza et al, 2012;Rubel et al, 2014). Moreover, another more recent study has demonstrated a role for α2β1 in inflammation during rheumatoid arthritis, with reduced disease severity in integrin α2 −/− mice (El Azreq et al, 2015).…”

Enhancing Integrin α1 Inserted (I) Domain Affinity to Ligand Potentiates Integrin α1β1-mediated Down-regulation of Collagen Synthesis

“…Interactions between cells with the surrounding extracellular matrix have emerged as a key factor involved in the initiation and progression to fibrosis (1). Integrins ␣1␤1 and ␣2␤1 are the key extracellular matrix receptors that regulate collagen turnover in many organs, including skin (2, 3) and kidneys (4,5). These integrins bind to collagens via their extracellular domains, resulting in the activation of intracellular signaling pathways via their cytoplasmic tails.…”