Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction.
Congenital obstructive nephropathy is a major cause of chronic kidney disease 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 model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud epithelium and podocytes using Foxd1Cre , Six2Cre , HoxB7Cre and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (mT/mG) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature and decreased renal blood flow. In addition, Foxd1-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of 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. Contra-lateral 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 chronic kidney disease.
Nagalakshmi, V.K., Li, M., Sha, S., Gigliotti, J.C., Klibanov, A.L., Epstein, F.H., Chevalier, R.L., Gomez, A., Sequeira-Lopez, M.L.S. Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction. Clinical Science, 132, 2519-2545. DOI: 10.1042/CS20180623