Remodeling of the Fetal Collecting Duct Epithelium

Abstract

Congenital urinary tract obstruction induces changes to the renal collecting duct epithelium, including alteration and depletion of intercalated cells. To study the effects of obstruction on the ontogeny of intercalated cell development, we examined normal and obstructed human fetal and postnatal kidneys. In the normal human fetal kidney, intercalated cells originated in the medullary collecting duct at 8 weeks gestation and remained most abundant in the inner medulla throughout gestation. In the cortex, intercalated cells were rare at 18 and 26 weeks gestation and observed at low abundance at 36 weeks gestation. Although early intercalated cells exhibit an immature phenotype, Type A intercalated cells predominated in the inner and outer medullae at 26 and 36 weeks gestation with other intercalated cell subtypes observed rarely. Postnatally, the collecting duct epithelium underwent a remodeling whereby intercalated cells become abundant in the cortex yet absent from the inner medulla. In 18-week obstructed kidneys with mild to moderate injury, the intercalated cells became more abundant and differentiated than the equivalent age-matched normal kidney. In contrast, more severely injured ducts of the late obstructed kidney exhibited a significant reduction in intercalated cells. These studies characterize the normal ontogeny of human intercalated cell development and suggest that obstruction induces premature remodeling and differentiation of the fetal collecting duct epithelium.

Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

“…In the fetal human and primate, obstruction is associated with reorganization and thickening of Coll IV expression in the tubular basement membranes, and with the formation of aSMA-positive peritubular collars. 1,3 In the UUO model, Coll IV and aSMApositive myofibroblasts also accumulate within the interstitium, but are more widely distributed throughout the interstitium. This difference likely reflects the more rapid onset and more severe injury caused by complete obstruction with ureteric ligation, compared with the more gradual progression invoked by partial or incomplete obstruction, as in fetal human congenital obstruction or in the fetal primate model of obstruction.…”

“…1 To replicate these conditions as closely as possible in the murine model of UUO, we counted intercalated cells in kidneys obstructed for 14 days. This prolonged obstruction resulted in a more significant reduction of intercalated cell numbers in the outer and inner medulla (decreases of 31% and 95%, respectively) similar to that in chronic human and primate fetal kidney obstruction.…”

“…1 Briefly, vATPase-positive cells were counted in collecting ducts of 3-and 14-day sham and obstructed kidneys and expressed as a percentage of the total number of cells per duct as determined by counting of DAPI-stained nuclei.…”

“…[1][2][3] Here, we demonstrate that despite the postnatal nature of the mouse UUO model, this model replicates many of the key pathogenic features of fetal obstruction, making it a suitable and powerful model for investigating early medullary and distal nephron injury.…”

“…In the fetus, obstruction of urinary flow during the critical stages of renal nephrogenesis alters branching morphogenesis, decreases nephron endowment, and disrupts normal tubulointerstitial development. [1][2][3][4] We have previously demonstrated that fetal obstruction in the human and primate kidney causes substantial medullary injury, including interstitial expansion, peritubular a smooth muscle actin (aSMA) collar formation, and collecting duct epithelial dysfunction. [1][2][3] Additional work is required to further identify how medullary and collecting duct injury contributes to and modulates the pathophysiology and progression of injury following obstruction.…”