Kidney failure in mice lacking the tetraspanin CD151

Abstract

The tetraspanin CD151 is a cell-surface molecule known for its strong lateral interaction with the laminin-binding integrin α3β1. Patients with a nonsense mutation in CD151 display end-stage kidney failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin α3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia. We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice. Furthermore, we generated podocyte-specific conditional knockout mice for the integrin α3 subunit that show renal defects similar to those in the Cd151 knockout mice. Our results support the hypothesis that CD151 plays a key role in strengthening α3β1-mediated adhesion in podocytes.

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

“…Mutations of CD151 in humans result in nephropathy with epidermolysis bullosa and deafness (Karamatic Crew et al 2004), while different phenotypes have been reported for cd151 À/À mice, including abnormal hemostasis , defective wound healing (Cowin et al 2006), and renal defects (Sachs et al 2006). Members of the tetraspanin family have been implicated in virus infection in animals and humans; in particular, different tetraspanins have been shown to act as receptors for HCV (Pileri et al 1998), HIV (von Lindern et al 2003), canine distemper virus (Loffler et al 1997), feline leukemia virus (Willett et al 1994), and porcine reproductive and respiratory syndrome virus (Shanmukhappa et al 2007); yet a recent report has also shown that members of the tetraspanin family, including CD151, protect human macrophages from HIV-1 and vescicular stomatitis virus infection, possibly by blocking virion binding/uptake (Ho et al 2006).…”

CD151 represses mammary gland development by maintaining the niches of progenitor cells

“…23,25 Targeted deletion or genetic mutation of CD151 partially impairs LB integrin-mediated tissue architecture and physiological functions. [28][29][30] Such in vivo function of CD151 appears to be linked to its ability to regulate branching morphogenesis and ECM dynamics in multiple cell types, including epithelial and endothelial cells. 24,31 While mice carrying the whole-body deletion of either a3 or a6 integrin are postnatally lethal, 7 the mice with whole-body deletion of the CD151 gene are viable and fertile, and exhibit a mild straindependent defect in kidney function.…”

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

“…The clinical relevance of the adhesome for podocyte function was recently demonstrated by the identification of mutations in the Integrin alpha3 gene, causing glomerular and skin disease in affected patients (10). In addition, other focal adhesome components such as INTEGRIN-beta1 and INTEGRIN-LINKED KINASE (ILK), as well as other core focal adhesome components, were identified to be critical for podocyte maintenance (11)(12)(13)(14)(15).…”