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

Abstract

Goligorsky MS. Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted. Am J Physiol Renal Physiol 298: F357-F364, 2010. First published November 11, 2009 doi:10.1152/ajprenal.00542.2009.-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. fibrosis; caveolin; AMD3100; mesenchymal stem cells GLOMERULOSCLEROSIS and tubulointerstitial scarring (TIS)-the main processes governing progression of chronic renal diseasesare well studied and described (3, 7-9, 11, 15). Unilateral ureteral obstruction (UUO) has been consistently utilized as a convenient model of TIS, although this process is much less pronounced in mice than in rats, rabbits, and dogs (5). This model has provided valuable insights into the molecular and cellular mechanisms of TIS progression. Specifically, the role of various subsets of infiltrating leukocytes, hypoxia, angiotensin II, transforming growth factor (TGF)-␤, TNF-␣, plasminogen activator inhibitor-1, and reactive oxygen species, to name a few, has been established (reviewed in Refs. 3,5,[7][8][9]11,15). Notwithstanding these advances, significant controvers...

A Murine Model of Irreversible and Reversible Unilateral Ureteric Obstruction

“…Irreversible UUO allows the study of inflammation and tissue injury including the role of various leukocytes and mediators [1][2][3]10 whilst study of the R-UUO model enables researchers to explore the resolution of renal injury and associated tissue remodeling. 6,7,[11][12][13][14][15] Other investigators have used different methods to induce and reverse ureteric obstruction. In the first description of the R-UUO model, the left ureter of male C57BL/6 mice was obstructed with an atraumatic microvascular clamp via a flank incision.…”

TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis

“…Although their origin is uncertain, myofibroblasts are probably derived (1) from resident interstitial fibroblasts (e.g., Picard et al 2008), (2) by Snai1- or Id1-dependent transcriptional reprogramming of renal pericytes or perivascular fibroblasts (Humphreys et al 2010; Cook 2010; Roufosse et al 2006; Lin et al 2008), (3) as a consequence of tubular epithelial-to-mesenchymal transdifferentiation (EMT; Yamashita et al 2005; Kalluri and Neilson 2003; Iwano et al 2002; Eddy 2009; Iwano and Neilson 2004; Liu 2006, 2010; Grande and Lopez-Novoa 2009), or (4) by extra-renal recruitment from the circulation or bone marrow (Ricardo et al 2008). Indeed, the mobilization of stem-like cells accompanies post-obstructive kidney regeneration suggesting that renal capsule-derived, hematopoietic, or mesenchymal progenitor cells participate in repair (Park et al 2010aPark et al 2010b; Yamashita et al 2005). Whether progenitor involvement has a positive or negative effect on outcome, however, is controversial, although renal-artery-delivered human mesenchymal stem cells appear to attenuate UUO-induced fibrosis (Asanuma et al 2010).…”

The Secretome of Hydrogel-Coembedded Endothelial Progenitor Cells and Mesenchymal Stem Cells Instructs Macrophage Polarization in Endotoxemia

“…The therapeutic delivery of stem cells has been demonstrated to enhance the repair and regeneration of the kidney after injury [1][2][3][4][5][6][7]. Although various multipotent stem cells have been examined for their repair potential, endothelial progenitor cells (EPCs) have demonstrated remarkable renoprotective potential.…”

“…However, during kidney and vascular injury, the competence of endogenous EPCs is often compromised, leading to accelerated progression of the injury [7]. Previous studies from our laboratory and others have shown that delivered EPCs counter the vascular impairment that occurs during the course of acute kidney injury (AKI) [1,6,7,11] and improve renal function, attenuate inflammation, decrease tubular and vascular damage, and enhance angiogenesis [1,4,6,7].…”