Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits
Wen Ding, … , Armando J. Mendez, Lina A. Shehadeh
Wen Ding, … , Armando J. Mendez, Lina A. Shehadeh
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e94818. https://doi.org/10.1172/jci.insight.94818.
View: Text | PDF
Research Article Metabolism Nephrology

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

  • Text
  • PDF
Abstract

Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr–/– mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration.

Authors

Wen Ding, Keyvan Yousefi, Stefania Goncalves, Bradley J. Goldstein, Alfonso L. Sabater, Amy Kloosterboer, Portia Ritter, Guerline Lambert, Armando J. Mendez, Lina A. Shehadeh

×

Figure 1

OPN expression is increased in Alport mice.

Options: View larger image (or click on image) Download as PowerPoint
OPN expression is increased in Alport mice.
(A) Osteopontin (OPN) expres...
(A) Osteopontin (OPN) expression is substantially elevated in the renal tubules of Alport versus wild-type (WT) mice as shown by immunostaining and confocal microscopy. Tubules+ stands for quantifications of OPN staining in tubules and peritubular capillaries. Images are representative of 6 mice per group. Scale bars: 20 μm. Western blots and corresponding densitometry show elevated OPN expression in Col4a3–/– versus WT or Col4a3+/– mouse kidneys (B) and plasma (C). n = 3–6 mice per group. Quantification is based on 3 independent experiments. Data are the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 based on ANOVA with Tukey’s post hoc test. n.d.u., normalized densitometry units.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts