Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted

Unilateral ureteral obstruction (UUO), a model of tubulointerstitial scarring (TIS), has a propensity toward regeneration of renal parenchyma after release of obstruction (RUUO). No information exists on the contribution of stem cells to this process. We performed UUO in FVB/N mice, reversed it afte...

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Published in:American Journal of Physiology - Renal Physiology 2010-02, Vol.298 (2), p.F357-F364
Main Authors: Park, H C, Yasuda, K, Ratliff, B, Stoessel, A, Sharkovska, Y, Yamamoto, I, Jasmin, J-F, Bachmann, S, Lisanti, M P, Chander, P, Goligorsky, M S
Format: Article
Language:English
Subjects:
Animals
Caveolin 1 - metabolism
Cell Division - drug effects
Chemokine CXCL12 - antagonists & inhibitors
Disease Progression
Enzyme Inhibitors - pharmacology
Fibrosis
Hematopoietic Stem Cells - pathology
Heterocyclic Compounds - pharmacology
Kidney - pathology
Kidney - physiopathology
Kidney Cortex - pathology
Male
Mesenchymal Stem Cells - pathology
Mice
Mice, Inbred Strains
Nitric Oxide Synthase - antagonists & inhibitors
omega-N-Methylarginine - pharmacology
Receptors, CXCR4 - antagonists & inhibitors
Recovery of Function
Regeneration
Stem Cells - pathology
Ureteral Obstruction - pathology
Ureteral Obstruction - physiopathology
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Summary:Unilateral ureteral obstruction (UUO), a model of tubulointerstitial scarring (TIS), has a propensity toward regeneration of renal parenchyma after release of obstruction (RUUO). No information exists on the contribution of stem cells to this process. We performed UUO in FVB/N mice, reversed it after 10 days, and examined kidneys 3 wk after RUUO. UUO resulted in attenuation of renal parenchyma. FACS analysis of endothelial progenitor (EPC), mesenchymal stem (MSC) and hematopoietic stem (HSC) cells obtained from UUO kidneys by collagenase-dispersed single-cell suspension showed significant increase in EPC, MSC, and HSC compared with control. After RUUO cortical parenchyma was nearly restored, and TIS score improved by 3 wk. This reversal process was associated with return of stem cells toward baseline level. When animals were chronically treated with nitric oxide synthase (NOS) inhibitor at a dose that did not induce hypertension but resulted in endothelial dysfunction, TIS scores were not different from control UUO, but EPC number in the kidney decreased significantly; however, parenchymal regeneration in these mice was similar to control. Blockade of CXCR4-mediated engraftment resulted in dramatic worsening of UUO and RUUO. Similar results were obtained in caveolin-1-deficient but not -overexpressing mice, reflecting the fact that activation of CXCR4 occurs in caveolae. The present data show increase in EPC, HSC, and MSC population during UUO and a tendency for these cells to decrease to control level during RUUO. These processes are minimally affected by chronic NOS inhibition. Blockade of CXCR4-stromal cell-derived factor-1 (SDF-1) interaction by AMD3100 or caveolin-1 deficiency significantly reduced the UUO-associated surge in stem cells and prevented parenchymal regeneration after RUUO. We conclude that the surge in stem cell accumulation during UUO is a prerequisite for regeneration of renal parenchyma.
ISSN:1931-857X
0363-6127
1522-1466
DOI:10.1152/ajprenal.00542.2009