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Developmental Biology - Precision Medicine|
Regrowing Damaged Kidneys
"During development, there are more precursor cells. Studying them may give us clues on how to push these cells to come awake in the adult and regenerate to maintain kidney function."
Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.
Nagalakshmi, Minghong Li, Soham Shah, Joseph C. Gigliotti, Alexander L. Klibanov, Frederick H. Epstein, Robert L. Chevalier, R. Ariel Gomez and Sequeira-Lopez.
The work was supported by the National Institutes of Health, grants DK091330, DK096373 and DK116196.
About the Journal: Clinical Science
Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. In addition to original papers, the journal features state-of-the-art review articles, hypotheses, invited commentaries and scientific correspondence on recently published papers appearing in the journal. Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health.
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Obstructive nephropathy is the leading identifiable cause of renal failure in children. However,
current management is limited to surgical removal of the obstruction, which often fails to prevent
progressive tissue damage. UVA research investigates the neonatal mouse, which parallels
urinary tract obstruction in the human fetus. Image: Fetal kidney branching, UVA.