title: Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted.
abstract: 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.
authors.affiliation: Departments of Medicine, Pharmacology, and Pathology, Renal Research Institute, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Park
authors.forename: K
authors.initials: K
authors.lastname: Yasuda
authors.forename: B
authors.initials: B
authors.lastname: Ratliff
authors.forename: A
authors.initials: A
authors.lastname: Stoessel
authors.forename: Y
authors.initials: Y
authors.lastname: Sharkovska
authors.forename: I
authors.initials: I
authors.lastname: Yamamoto
authors.forename: J-F
authors.initials: JF
authors.lastname: Jasmin
authors.forename: S
authors.initials: S
authors.lastname: Bachmann
authors.forename: M P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: P
authors.initials: P
authors.lastname: Chander
authors.forename: M S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D000818:Animals; D001596:Benzylamines; D051242:Caveolin 1 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors; D000080027:Cyclams; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology*; D007672:Kidney Cortex / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D020127:Recovery of Function; D012038:Regeneration; D013234:Stem Cells / Q000473:pathology*; D014517:Ureteral Obstruction / Q000473:pathology* / Q000503:physiopathology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001596:Benzylamines; D051242:Caveolin 1; D054377:Chemokine CXCL12; D000080027:Cyclams; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; C088327:plerixafor