Formation of atubular glomeruli in the developing kidney following chronic urinary tract obstruction

Abstract

Congenital urinary tract obstruction is a major cause of progressive renal disease in children. We developed a model of partial unilateral ureteral obstruction (UUO) in the neonatal mouse, in which nephrogenesis at birth is similar to that of the midtrimester human fetus. The proximal tubule responds to UUO by undergoing apoptosis and necrosis, likely due to mitochondrial sensitivity to hypoxia and reactive oxygen species in the face of reduced endogenous antiapoptotic factors such as eNOS. Damage to the glomerulotubular junction is followed by scission and formation of atubular glomeruli and aglomerular tubules. This is an orchestrated process, with atubular glomeruli surrounded by a continuous layer of regenerated parietal epithelial cells. Relief of UUO at 7 days of age results in remodeling of the renal parenchyma by adulthood. In contrast to proximal tubular destruction, collecting ducts remain dilated and patent, with remodeling due to apoptosis and proliferation (a process associated with recruitment of intercalated cells as progenitor cells following UUO in the fetal monkey). Formation of atubular glomeruli occurs in other renal disorders (congenital nephrotic syndrome and cystinosis), and may represent a maladaptive response to proximal tubular injury reflecting an evolutionary adaptation by an ancestor we share with aglomerular marine fish.