SDF-1 activates papillary label-retaining cells during kidney repair from injury

Abstract

The adult kidney contains a population of low-cycling cells that resides in the papilla. These cells retain for long periods S-phase markers given as a short pulse early in life; i.e., they are label-retaining cells (LRC). In previous studies in adult rat and mice, we found that shortly after acute kidney injury many of the quiescent papillary LRC started proliferating (Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q. J Am Soc Nephrol 20: 2315–2327, 2009; Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q. J Clin Invest 114: 795–804, 2004) and, with cell-tracking experiments, we found upward migration of some papillary cells including LRC (Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q. J Am Soc Nephrol 20: 2315–2327, 2009). To identify molecular cues involved in the activation (i.e., proliferation and/or migration) of the papillary LRC that follows injury, we isolated these cells from the H2B-GFP mice and found that they migrated and proliferated in response to the cytokine stromal cell-derived factor-1 (SDF-1). Moreover, in a papillary organ culture assay, the cell growth out of the upper papilla was dependent on the interaction of SDF-1 with its receptor Cxcr4. Interestingly, location of these two proteins in the kidney revealed a complementary location, with SDF-1 being preferentially expressed in the medulla and Cxcr4 more abundant in the papilla. Blockade of Cxcr4 in vivo prevented mobilization of papillary LRC after transient kidney ischemic injury and worsened its functional consequences. The data indicate that the SDF-1/Cxcr4 axis is a critical regulator of papillary LRC activation following transient kidney injury and during organ repair.

CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

“…However, plerixafor has been reported to worsen renal function following AKI when administered continuously by an Alzet minipump at 21 mg·kg Ϫ1 ·day Ϫ1 starting 24 h before ischemic clamping and continuing for 8 days postreperfusion (50). This is consistent with observations in a mouse model of myocardial infarction in which continuous CXCR4 blockade increased adverse cardiac remodeling (28).…”

“…CXCL12/SDF-1 is detected in the distal nephron in the normal kidney (arrow, Fig. 8A), as reported by others (50,59). CXCL12 continues to be expressed in these nephron segments 2 h postreperfusion (arrow , Fig.…”

SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution

“…We extended these studies to another species and found that a similar induction of SDF1 occurs in kidney cortex mRNA and in isolated CCDs from rabbits fed an acid diet for 3 days (Figure 1). We had previously found that SDF1 and its receptor CXCR4 are widely expressed in the kidney (9).…”

Role of medullary progenitor cells in epithelial cell migration and proliferation

“…Both CXCR4 and CXCR7 have been shown to play vital roles in tissue regeneration and renal function improvement as well as being required for transendothelial migration (28). The SDF-1/CXCR4 axis is involved in papillary label-retaining cell (LRC) activation after AKI (33). The presence of both chemokine receptors on our MPCs indicates a possible role of SDF-1 as a local mediator in the epithelial cell trans-differentiation of MPCs.…”