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Abstract: TH-OR17

Critical Role of Osteopontin in Maintaining Urinary Phosphate Solubility in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Jansson, Kyle, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Zhang, Shiqin, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Fields, Timothy A., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Rowe, Peter S. N., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Stubbs, Jason R., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

The loss of functional nephrons dramatically increases tubular phosphate concentrations in residual nephrons to levels that exceed supersaturation. Osteopontin (OPN), a SIBLING protein expressed by epithelial cells of the distal nephron, is known to enhance calcium-phosphate solubility in vitro; however, the role of OPN in maintaining tubular mineral solubility in CKD remains undefined.

Methods

We used CKD mouse models to determine: (1) the expression and timing of kidney/urine OPN changes in relation to mineral metabolism and kidney function markers, (2) the differential effects of tubular injury and acute nephron reduction on OPN expression, (3) how OPN deficiency alters kidney mineral deposition in CKD, and (4) how neutralization of the mineral-binding (ASARM) motif of OPN alters kidney mineralization and injury in phosphaturic mice.

Results

OPN protein expression is markedly increased in all tubular segments in mouse models of cystic kidney disease (pcy/pcy), glomerulonephritis (Col4a3-/-), and chronic tubulointerstitial injury (aristolochic acid). In Col4a3-/- mice with slowly progressive CKD, kidney OPN expression and urinary OPN:Cr increased before gross histologic changes in the kidney or a rise in BUN, serum Cr, FGF23 and PTH. Unilateral nephrectomy studies in wild-type mice proved that nephron reduction alone was sufficient to increase tubular OPN production. Induction of CKD in OPN-null mice fed a high phosphate diet led to severe nephrocalcinosis (Figure 1). Lastly, pharmacologic neutralization of the ASARM motif of OPN in phosphaturic (Hyp) mice resulted in severe nephrocalcinosis that mimicked OPN-null CKD mice.

Conclusion

Tubular OPN expression is increased in very early CKD and nephron loss alone is sufficient to induce these changes. OPN serves a key biological function to maintain tubular phosphate solubility in CKD.

Figure 1. Induction of CKD in Spp1-/- (OPN-null) mice results in severe nephrocalcinosis. Whole kidney μCT images demonstrating severe nephrocalcinosis in Spp1-/- mice fed a high phosphate (1.1%) diet following CKD induction by either ingestion of 0.2% adenine or IP injections of aristolochic acid.