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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.
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Research Article Metabolism Nephrology

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

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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

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Figure 4

OPN deficiency attenuates tendency for lenticonus in Col4a3–/– mice.

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OPN deficiency attenuates tendency for lenticonus in Col4a3–/– mice.
(A)...
(A) Schematic of optical coherence tomography (OCT) measurements studied. ACD, anterior chamber depth; CCT, central corneal thickness; ACAA, anterior capsule apical angle. (B and C) OCT measurements show that ACD and CCT are unaltered with OPN deficiency, while ACAA is significantly increased in Alport osteopontin-deficient (OPN-deficient) mice relative to Alport mice. n = 3–10 mice per group. Data are the mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001 based on ANOVA with Tukey’s post hoc test. (D) Electron microscopy shows thickened basement membrane of retinal capillaries in Col4a3–/– mice — a pathology that is reduced with OPN deficiency. Insets are shown at a higher magnification on the bottom. Yellow arrows point to basement membrane.

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