Critical Role of Osteopontin in Maintaining Urinary Phosphate Solubility in CKD. Issue 9 (29th September 2022) - Stubbs, Jason R.
Visual Abstract: Abstract : Key Points: Osteopontin (OPN) is highly expressed by tubular epithelial cells in CKD and functions to maintain calcium-phosphate solubility in tubular fluid. Reduced functional nephrons alone, in the absence of kidney injury, is sufficient to stimulate OPN expression by tubular epithelial cells. High levels of tubular fluid phosphate or the presence of phosphate-based crystals may stimulate tubular OPN production in CKD. Background: Nephron loss dramatically increases tubular phosphate to concentrations that exceed supersaturation. Osteopontin (OPN) is a matricellular protein that enhances mineral solubility in solution; however, the role of OPN in maintaining urinary phosphate solubility in CKD remains undefined. Methods: Here, we examined ( 1 ) the expression patterns and timing of kidney/urine OPN changes in CKD mice, ( 2 ) if tubular injury is necessary for kidney OPN expression in CKD, ( 3 ) how OPN deletion alters kidney mineral deposition in CKD mice, ( 4 ) how neutralization of the mineral-binding (ASARM) motif of OPN alters kidney mineral deposition in phosphaturic mice, and ( 5 ) the in vitro effect of phosphate-based nanocrystals on tubular epithelial cell OPN expression. Results: Tubular OPN expression was dramatically increased in all studied CKD murine models. Kidney OPN gene expression and urinary OPN/Cr ratios increased before changes in traditional biochemical markers of kidney function. Moreover, a reduction of nephron numbers alone (by unilateral nephrectomy) was sufficient to induce OPN expression in residual nephrons and induction of CKD in OPN-null mice fed excess phosphate resulted in severe nephrocalcinosis. Neutralization of the ASARM motif of OPN in phosphaturic mice resulted in severe nephrocalcinosis that mimicked OPN-null CKD mice. Lastly, in vitro experiments revealed calcium-phosphate nanocrystals to induce OPN expression by tubular epithelial cells directly. Conclusions: Kidney OPN expression increases in early CKD and serves a critical role in maintaining tubular mineral solubility when tubular phosphate concentrations are exceedingly high, as in late-stage CKD. Calcium-phosphate nanocrystals may be a proximal stimulus for tubular OPN production.