Overexpression of Notch Signaling in Renin Cells Leads to a Polycystic Kidney Phenotype

Polycystic kidney disease (PKD) is an inherited disorder that results in large kidneys, numerous fluid-filled cysts, and ultimately end stage kidney disease.  PKD is either autosomal dominant caused by mutations in PKD1 or PKD2 genes or autosomal recessive caused by mutations in the PKHD1 or DZIP1L genes.  While the genetic basis of PKD is known, the downstream molecular mechanisms and signaling pathways which lead to deregulation of proliferation, apoptosis, and differentiation are not completely understood.  The Notch pathway plays critical roles during kidney development including directing differentiation of various progenitor cells, and aberrant Notch signaling results in gross alternations in cell fate.  In this study, we generated and studied transgenic mice which have overexpression of an intracellular fragment of mouse Notch1 (“NotchIC”) in renin-expressing cells.  Mice with overexpression of NotchIC in renin-expressing cells developed numerous fluid-filled cysts, enlarged kidneys, anemia, renal insufficiency, and early death.  Cysts developed in both glomeruli and proximal tubules, had increased proliferation marks, and had increased levels of Myc.  This work implicates the Notch signaling pathway as a central player in PKD pathogenesis and suggests the Notch-Myc axis may be an important target for therapeutic intervention.