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Exp Mol Pathol. 2018 Aug;105(1):120-129. doi: 10.1016/j.yexmp.2018.07.001. Epub 2018 Jul 6.

Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome.

Author information

1
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA. Electronic address: kananoshiro@gmail.com.
2
Department of Pathology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
3
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA.
4
Division of Nephrology, Department of Pediatrics & Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, 1540 E Hospital Dr SPC 4259, Ann Arbor, MI 48109, USA.
5
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200, MD, Maastricht, the Netherlands.
6
Division of Nephrology, Department of Internal Medicine, University of Michigan, 1560 MSRB II, 1150 West Medical Center Drive, SPC5676, Ann Arbor, MI 48109, USA.

Abstract

BACKGROUND:

Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney.

METHODS:

We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18).

RESULTS:

Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p <0.001). TI MGP expression strongly correlated with interstitial fibrosis, tubular atrophy, acute tubular injury, and interstitial inflammation, independent of eGFR. Kaplan-Meier analysis and multivariable Cox regression showed that higher levels of TI MGP expression were associated with an increased risk for the composite of 40% decline in eGFR and end-stage renal disease (ESRD) (HR, 3.31; 95% CI, 1.31 to 6.32; p =0.02). Glomerular and tubulointerstitial cells demonstrated nuclear and cytoplasmic cMGP and ucMGP staining, and eGFR inversely correlated with quantified glomerular cMGP staining (p <0.05).

CONCLUSIONS:

Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action.

KEYWORDS:

Chronic kidney disease; Gene expression; Matrix gla protein; Renal outcome; Vitamin K

PMID:
29981754
PMCID:
PMC6167754
DOI:
10.1016/j.yexmp.2018.07.001
[Indexed for MEDLINE]
Free PMC Article

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