Podocyte Injury–Driven Lipid Peroxidation Accelerates the Infiltration of Glomerular Foam Cells in Focal Segmental Glomerulosclerosis

Hara, Satoshi; Kobayashi, Naho; Sakamoto, Kazuo; Ueno, Toshiharu; Manabe, Shun; Takashima, Yasutoshi; Hamada, Juri; Pastan, Ira; Fukamizu, Akiyoshi; Matsusaka, Taiji; Nagata, Michio

doi:10.1016/j.ajpath.2015.04.007

Cited by 43 publications

(40 citation statements)

References 56 publications

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“…8 In a series of Miniature Schnauzer dogs, hyperlipidemia was associated with the presence of glomerular foam cells (observed with TEM), but glomerular lipid thromboemboli were more common than were dilated loops filled with foam cells. 5 Further studies are required to determine the association between hyperlipidemia and glomerular foam cell accumulation in dogs.…”

Section: Discussionmentioning

confidence: 99%

Glomerular Lipidosis in Dogs

et al. 2017

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Glomerular lipidosis (GL) is characterized by dilated glomerular capillary loops containing lipid-laden cells (foam cells). Previously, GL was considered to be an incidental finding because affected dogs were typically not azotemic. However, the International Renal Interest Society staging system for canine chronic kidney disease has increased the awareness of other clinical parameters (eg, proteinuria and hypertension) that should be included in the assessment of renal function. As such, the aim of this study was to determine clinical abnormalities and concurrent renal lesions in dogs with GL. GL was identified in renal biopsies from 46 dogs evaluated by the International Veterinary Renal Pathology Service. GL was the sole diagnosis in 5 of 46 cases (11%), all of which were proteinuric. All 5 dogs had at least 1 additional clinicopathologic abnormality consistent with renal disease, including hypertension (4), azotemia (3), and/or hypoalbuminemia (2). The remaining 41 dogs had GL in combination with other glomerular lesions, the most common being focal segmental glomerulosclerosis (16, 35%), lesions consistent with juvenile nephropathy (8, 17%), and glomerular amyloidosis (5, 11%). Overall, dogs with severe GL were younger than were those with mild GL (P < .001). The percentage of glomeruli affected by GL differed by concurrent diagnoses (P = .034), with the highest percentage of affected glomeruli in dogs with GL alone or those with concurrent juvenile nephropathy. These findings suggest that GL should be a recognized histologic phenotype of glomerular injury associated with clinical renal dysfunction and/or juvenile nephropathies.

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Section: Discussionmentioning

confidence: 99%

Glomerular Lipidosis in Dogs

et al. 2017

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“…Several studies have demonstrated the importance of the inflammatory milieu in the foam cell formation [91,134,135]. Cytokines such as TNFα and IL-1β can modify LDL receptor-mediated…”

Section: The Fatty Kidney In Dnmentioning

confidence: 99%

“…Increased podocyte detachment has been observed in patients with obesity related-glomerulopathy, focal segmental glomerulosclerosis (FSGS), and DN [90]. In this regard, podocytopenia could be mediated by alterations in the lipid balance [90,91].…”

Section: Lipotoxicity In Renal Cellsmentioning

confidence: 99%

“…The sterol regulatory element-binding proteins (SREBPs) are the main transcription factors associated with lipid metabolism through their direct role in renal lipid accumulation [84]. Upregulated SREBP expression is found in lipid droplets loaded podocytes, both in experimental studies and in a retrospective analysis of renal biopsies of patients with DN or obesity-related glomerulopathy [7,91,92]. Intracellular lipid is imbalanced towards accumulation when lipid efflux is impaired.…”

Section: Lipotoxicity In Renal Cellsmentioning

confidence: 99%

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Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

190

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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“…We speculate that increased PLA2 activity in damaged podocytes and/or tubular epithelial cells may cause higher urinary concentrations of LPC and FA. Recently, a mouse model of FSGS induced by podocyte-specific injury of a double transgenic mouse (NEP25/LDLR-/-) with severe hypercholesterolemia displayed glomerular lipid peroxidation, foam-cell formation, and glomerular accumulation of LPC [31]. …”

Section: Discussionmentioning

confidence: 99%

Distinct urinary lipid profile in children with focal segmental glomerulosclerosis

et al. 2015

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Background Focal segmental glomerulosclerosis (FSGS) accounts for the majority of new-onset end-stage renal disease (ESRD) during adolescence. FSGS treatment is a great challenge for pediatric nephrologists due to intertwined molecular pathways underlining its complex pathophysiology. There is emerging evidence showing that perturbed lipid metabolism plays a role in the pathophysiology of FSGS. Methods We postulate that the nephrotic milieu in FSGS differs from minimal change disease (MCD) and that urinary lipidomics can be used as a tool for early diagnosis of FSGS. We explored the urinary lipid profile of patients with FSGS and MCD using an unbiased metabolomics approach. Results We discovered a unique lipid signature characterized by increased concentration of fatty acid (FA) and lysophosphatidylcholines (LPC) and a decrease in urinary concentration of phosphatidylcholine (PC) in patients with FSGS. These findings indicate increased metabolism of membrane phospholipid PC by phospholipase A2 (PLA2), resulting in higher urinary concentrations of LPC and FA. Conclusions We propose that increased PC by-products can be used as a biomarker to diagnose FSGS and shed light on the mechanism of tubular and podocyte damage. Validation of identified urinary lipids as a biomarker in predicting the diagnosis and progression of FSGS in a larger patient population is warranted.

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Podocyte Injury–Driven Lipid Peroxidation Accelerates the Infiltration of Glomerular Foam Cells in Focal Segmental Glomerulosclerosis

Cited by 43 publications

References 56 publications

Glomerular Lipidosis in Dogs

Glomerular Lipidosis in Dogs

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Distinct urinary lipid profile in children with focal segmental glomerulosclerosis

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