Netrin-1 Overexpression Induces Polycystic Kidney Disease: A Novel Mechanism Contributing to Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.

Riyaz Mohamed, Yang Liu, Andreas D Kistler, Peter C Harris, Muthusamy Thangaraju

The American journal of pathology 2022 Jun

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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. Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Citation

Riyaz Mohamed, Yang Liu, Andreas D Kistler, Peter C Harris, Muthusamy Thangaraju. Netrin-1 Overexpression Induces Polycystic Kidney Disease: A Novel Mechanism Contributing to Cystogenesis in Autosomal Dominant Polycystic Kidney Disease. The American journal of pathology. 2022 Jun;192(6):862-875