Critical Role of Osteopontin in Maintaining Urinary Phosphate Solubility in CKD.

Autor:	Stubbs JR; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas., Zhang S; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Jansson KP; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas., Fields TA; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas., Boulanger J; Sanofi Genzyme, Cambridge, Massachusetts., Liu S; Sanofi Genzyme, Cambridge, Massachusetts., Rowe PS; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Jazyk:	angličtina
Zdroj:	Kidney360 [Kidney360] 2022 Jun 22; Vol. 3 (9), pp. 1578-1589. Date of Electronic Publication: 2022 Jun 22 (Print Publication: 2022).
DOI:	10.34067/KID.0007352021
Abstrakt:	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. Competing Interests: J. Boulanger reports being an employee of Sanofi-Genzyme. S. Liu reports being an employee of Sanofi-Genzyme and ownership interest in Sanofi. P.S. Rowe reports ownership interest in Apple (AAPL), CYBL, DWAC, and RTX, and patents or royalties from the University of Kansas Medical Center. J.R. Stubbs reports consultancy agreements with Novadiol; research funding from Genzyme; and being a scientific advisor for Spectradyne LLC. All remaining authors have nothing to disclose. (Copyright © 2022 by the American Society of Nephrology.)
Databáze:	MEDLINE
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