Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation

Souza, Ana C. P.; Bocharov, Alexander V.; Baranova, Irina N.; Vishnyakova, Tatyana G.; Huang, Yuning; Wilkins, Kenneth J.; Hu, Xiaobang; Street, Jonathan M.; Álvarez-Prats, Alejandro; Mullick, Adam E.; Patterson, Amy P.; Remaley, Alan T.; Eggerman, Thomas L.; Yuen, Peter S.T.; Star, Robert A.

doi:10.1016/j.kint.2015.12.043

Cited by 64 publications

(49 citation statements)

References 53 publications

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“…Previous studies in cultured proximal tubule epithelial cells (PTECs) showed that CD36 activation leads to oxidative stress, apoptosis, and pro-fibrotic signalling (fibronectin expression, TGF-β release) [44–46]. Similarly, mice deficient in CD36 are resistant to renal fibrosis and oxidative stress in unilateral ureteral obstruction [46,47]. Our data also support a role for CD36 in PTEC fibrogenesis through the stimulation of p38 MAPK and TGF-β receptor-mediated activation of Smad3, collagen type IV and fibronectin.…”

Section: Discussionmentioning

confidence: 99%

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

Munkonda

Akbari

Landry

et al. 2018

J of Extracellular Vesicle

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Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100–1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes. The purpose of the present study was to examine the role of podocyte MPs in tubular epithelial cell fibrotic responses. MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured human proximal tubule epithelial cells (PTECs). Treatment with podocyte MPs increased p38 and Smad3 phosphorylation and expression of the extracellular matrix (ECM) proteins fibronectin and collagen type IV. MP-induced responses were attenuated by co-treatment with the p38 inhibitor SB202190. A transforming growth factor beta (TGF-β) receptor inhibitor (LY2109761) blocked MP-induced Smad3 phosphorylation and ECM protein expression but not p38 phosphorylation suggesting that these responses occurred downstream of p38. Finally, blockade of the class B scavenger receptor CD36 completely abrogated MP-mediated p38 phosphorylation, downstream Smad3 activation and fibronectin/collagen type IV induction. Taken together our results suggest that podocyte MPs interact with proximal tubule cells and induce pro-fibrotic responses. Such interactions may contribute to the development of tubular fibrosis in glomerular disease.

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Section: Discussionmentioning

confidence: 99%

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

Munkonda

Akbari

Landry

et al. 2018

J of Extracellular Vesicle

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show abstract

“…A study by Okamura et al (26) showed a protective role for CD36 deletion in renal fibrogenesis induced by unilateral ureteral obstruction, through attenuating the proinflammatory pathway. A novel peptide that antagonizes CD36 was recently reported to ameliorate renal inflammation and tubulointerstitial fibrosis, and slow the progression of CKD in the mouse model of unilateral ureteral obstruction and 5/6 nephrectomy (46). Despite this body of evidence, key questions about CD36 as a fatty acid transporter involved in the development of obesity-related CKD are unanswered.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory stress promotes the development of obesity-related chronic kidney disease via CD36 in mice

Yang

Xiao

Luo

et al. 2017

Journal of Lipid Research

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Ectopic fat located in the kidney has emerged as a novel cause of obesity-related chronic kidney disease (CKD). In this study, we aimed to investigate whether inflammatory stress promotes ectopic lipid deposition in the kidney and causes renal injury in obese mice and whether the pathological process is mediated by the fatty acid translocase, CD36. High-fat diet (HFD) feeding alone resulted in obesity, hyperlipidemia, and slight renal lipid accumulation in mice, which nevertheless had normal kidney function. HFD-fed mice with chronic inflammation had severe renal steatosis and obvious glomerular and tubular damage, which was accompanied by increased CD36 expression. Interestingly, CD36 deficiency in HFD-fed mice eliminated renal lipid accumulation and pathological changes induced by chronic inflammation. In both human mesangial cells (HMCs) and human kidney 2 (HK2) cells, inflammatory stress increased the efficiency of CD36 protein incorporation into membrane lipid rafts, promoting FFA uptake and intracellular lipid accumulation. Silencing of CD36 in vitro markedly attenuated FFA uptake, lipid accumulation, and cellular stress induced by inflammatory stress. We conclude that inflammatory stress aggravates renal injury by activation of the CD36 pathway, suggesting that this mechanism may operate in obese individuals with chronic inflammation, making them prone to CKD.

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“…These observations suggest that CD36 is indiscriminate in its binding of LCFA, similar to albumin or the intracellular fatty acid‐binding protein (Schumann & Fuhrmann, ). Souza et al () reported that CD36 seems to play a role in progression of renal disease by causing dyslipidemia in experimental chronic kidney disease.…”

Section: Discussionmentioning

confidence: 99%

Palmitate induces mitochondrial superoxide generation and activates AMPK in podocytes

Lee¹,

Choi²,

Lee³

2017

Journal Cellular Physiology

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Studies have shown that high levels of serum free fatty acids (FFAs) are associated with lipotoxicity and type 2 diabetes. Palmitic acid (PA) is the predominant circulating saturated FFA, yet its role in the pathogenesis of diabetic nephropathy (DN) is not clear. Recently, one study suggested that mitochondrial superoxide production is related to AMP-activated protein kinase (AMPK) activity in diabetic mice kidneys. To elucidate the link between PA and oxidative stress and AMPK activity in DN, we compared the cultured murine podocytes exposed to PA and oleic acid (OA). Incubation of cells with 250 μM PA or OA induced a translocation of CD36, a fatty acid transport protein, with intracellular lipid accumulation. PA, but not OA, induced mitochondrial superoxide and hydrogen peroxide (H O ) generation in podocytes, as shown by enhanced fluorescence of MitoSOX Red and dichlorofluorescein (DCF), respectively. Costimulation of PA-treated cells with the H O scavenger catalase abolished the PA-induced DCF fluorescence. Only PA induced mitochondrial damage as shown by electron microscopy. The AMPK activity was determined by immunoblotting, measuring the ratio of phosphorylated AMPK (p-AMPK) to total AMPK. Only PA significantly increased the p-AMPK levels compared with controls. Addition of catalase to PA-treated cells did not affect the PA-stimulated p-AMPK levels. Collectively, our results indicate that PA induces mitochondrial superoxide and H O generation in cultured podocytes, which may not be directly linked to AMPK activation. Given that, PA seems to play an important role in the pathogenesis of DN through lipotoxicity initiated by mitochondrial superoxide overproduction.

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Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation

Cited by 64 publications

References 53 publications

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

Inflammatory stress promotes the development of obesity-related chronic kidney disease via CD36 in mice

Palmitate induces mitochondrial superoxide generation and activates AMPK in podocytes

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