| First Author | Mohamed R | Year | 2022 |
| Journal | Am J Pathol | Volume | 192 |
| Issue | 6 | Pages | 862-875 |
| PubMed ID | 35358475 | Mgi Jnum | J:339410 |
| Mgi Id | MGI:7311150 | Doi | 10.1016/j.ajpath.2022.03.004 |
| Citation | Mohamed R, et al. (2022) Netrin-1 Overexpression Induces Polycystic Kidney Disease: A Novel Mechanism Contributing to Cystogenesis in Autosomal Dominant Polycystic Kidney Disease. Am J Pathol 192(6):862-875 |
| abstractText | Despite recent advances in understanding the pathogenesis of polycystic kidney disease (PKD), the underlying molecular mechanisms involved in cystogenesis are not fully understood. This study describes a novel pathway involved in cyst formation. Transgenic mice overexpressing netrin-1 in proximal tubular cells showed increased production and urinary excretion of netrin-1. Although no cysts were detectable immediately after birth, numerous small cysts were evident by the age of 4 weeks, and disease was accelerated along with age. Surprisingly, cyst formation in the kidney was restricted to male mice, with 80% penetrance. However, ovariectomy induced kidney cyst growth in netrin-1-overexpressing female mice. Cyst development in males was associated with albuminuria and polyuria and increased cAMP excretion in netrin-1 transgenic mice. Netrin-1 overexpression significantly increased extracellular signal-regulated kinase and focal adhesion kinase phosphorylation and vimentin expression. Interestingly, p53 expression was increased but in an inactive form. Furthermore, netrin-1 expression was increased in cystic epithelia and urine of various rodent models of PKD. siRNA-mediated suppression of netrin-1 significantly reduced cyst growth and improved kidney function in netrin-1 transgenic mice and in two genetic animal models of PKD. Together, these data demonstrate that netrin-1 up-regulation induced cyst formation in autosomal dominant PKD. |
