Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

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.

Osteopontin Expression in Cardiomyocytes Is Increased in Pediatric Patients With Sepsis or Pneumonia

“…Table 1 lists demographic data for autopsy cases used for this study. These kidney tissues (especially the diseased one) were used as positive controls for OPN expression as it is known that renal tubular cells express high levels of OPN under pathological conditions (Ding et al, 2018).…”

“…Osteopontin (OPN) is a matricellular protein synthesized by a range of tissues and cell types including immunological cells (macrophages and T cells) (Lund et al, 2009), fibroblasts (Ashizawa et al, 1996; Jin et al, 2011), epithelial cells (Kato et al, 2014), osteoclasts, and osteoblasts (Qing et al, 2014), vascular smooth muscle cells (Sodhi et al, 2001), renal tubular epithelial cells (Zhang et al, 2010; Cobbs et al, 2018; Ding et al, 2018), and cardiomyocytes (Ashizawa et al, 1996; Lorenzen et al, 2015). OPN has been implicated as an important regulator of inflammation, biomineralization, cellular viability, cancer, diabetes, and renal disease (Icer and Gezmen-Karadag, 2018), and in the last few years has been getting increasing attention in the cardiovascular field (Singh et al, 2014; Li et al, 2017; Icer and Gezmen-Karadag, 2018).…”

Reactive Oxygen Species and Oxidative Stress in the Pathogenesis and Progression of Genetic Diseases of the Connective Tissue

“…In hearts, the expression of Hbb-b1, Alas2, Cnn1, Aqp7, and Ogdhl genes was significantly reduced in Col4a3 −/− mice [ 101 ]. In addition, defective mitochondrial respiration has been observed in primary tubular cells and in cardiomyocytes isolated from Col4a3 −/− mice, as measured by oxygen flux analysis [ 102 ]. Electron microscopy images revealed stressed mitochondrial morphology in the Alport tubular renal cells and hearts [ 101 , 102 ].…”

“…In addition, defective mitochondrial respiration has been observed in primary tubular cells and in cardiomyocytes isolated from Col4a3 −/− mice, as measured by oxygen flux analysis [ 102 ]. Electron microscopy images revealed stressed mitochondrial morphology in the Alport tubular renal cells and hearts [ 101 , 102 ]. In this context, two therapeutic approaches were taken with similar results.…”

“…Treatment of Col4a3 −/− mice with anti-miR 21 that directly targets Mpv17l in kidney increases lifespan and protects Col4a3 −/− mice from kidney disease progression by preventing miR-21-mediated suppression of the PPARα fatty acid metabolism and mitochondrial biogenesis pathways and inhibition of mitochondrial ROS generation in the kidney [ 100 ]. Similarly, osteopontin deficiency improves renal function and mitochondrial respiration in the renal tubules, which reduces dynamin-3 expression [ 102 ] and the cardiac phenotype and myocardial mitochondrial respiration by rescue of 2-oxoglutarate dehydrogenase-like protein (OGHDL) expression [ 101 ].…”