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Clin Sci (Lond). 2018 Dec 5;132(23):2519-2545. doi: 10.1042/CS20180623. Print 2018 Dec 12.

Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction.

Author information

1
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, U.S.A.
2
Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, VA, U.S.A.
3
Department of Integrated Physiology and Pharmacology, Liberty University College of Osteopathic Medicine, Lynchburg, VA, U.S.A.
4
Cardiovascular Division, University of Virginia Health System, VA, U.S.A.
5
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, U.S.A. msl7u@virginia.edu.

Abstract

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.

KEYWORDS:

kidney regeneration; lineage tracing; nephrovascular development; obstructive nephropathy; renal progenitors

PMID:
30442812
PMCID:
PMC6415776
[Available on 2019-12-12]
DOI:
10.1042/CS20180623
[Indexed for MEDLINE]

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