Lysosomal regulation of extracellular vesicle excretion during d-ribose-induced NLRP3 inflammasome activation in podocytes

Ji, Hong; Bhat, Owais M.; Li, Guangbi; Dempsey, Sara K.; Zhang, Qinghua; Ritter, Joseph K.; Li, Weiwei; Li, Pin‐Lan

doi:10.1016/j.bbamcr.2019.02.007

Cited by 40 publications

(46 citation statements)

References 51 publications

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“…Small extracellular vesicles were isolated by differential ultracentrifugation from CASMC culture medium as described previously . As mentioned above, after 70%‐80% confluence, CASMCs were incubated with or without P i (3 mmol/L) and also with ASM inhibitor amitriptyline (20 μmol/L) for 24 hours. Cell medium was collected and centrifuged at 300 g at 4°C for 10 minutes to remove detached cells.…”

Section: Methodsmentioning

confidence: 99%

Medial calcification in the arterial wall of smooth muscle cell‐specific Smpd1 transgenic mice: A ceramide‐mediated vasculopathy

Bhat

Yuan

Cain

et al. 2019

J Cellular Molecular Medi

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Arterial medial calcification (AMC) is associated with crystallization of hydroxyapatite in the extracellular matrix and arterial smooth muscle cells (SMCs) leading to reduced arterial compliance. The study was performed to test whether lysosomal acid sphingomyelinase (murine gene code: Smpd1)‐derived ceramide contributes to the small extracellular vesicle (sEV) secretion from SMCs and consequently leads to AMC. In Smpd1trg/SMcre mice with SMC‐specific overexpression of Smpd1 gene, a high dose of Vit D (500 000 IU/kg/d) resulted in increased aortic and coronary AMC, associated with augmented expression of RUNX2 and osteopontin in the coronary and aortic media compared with their littermates (Smpd1trg/SMwt and WT/WT mice), indicating phenotypic switch. However, amitriptyline, an acid sphingomyelinase (ASM) inhibitor, reduced calcification and reversed phenotypic switch. Smpd1trg/SMcre mice showed increased CD63, AnX2 and ALP levels in the arterial wall, accompanied by reduced co‐localization of lysosome marker (Lamp‐1) with multivesicular body (MVB) marker (VPS16), a parameter for lysosome‐MVB interaction. All these changes related to lysosome fusion and sEV release were substantially attenuated by amitriptyline. Increased arterial stiffness and elastin disorganization were found in Smpd1trg/SMcre mice as compared to their littermates. In cultured coronary arterial SMCs (CASMCs) from Smpd1trg/SMcre mice, increased Pi concentrations led to markedly increased calcium deposition, phenotypic change and sEV secretion compared with WT CASMCs, accompanied by reduced lysosome‐MVB interaction. However, amitriptyline prevented these changes in Pi‐treated CASMCs. These data indicate that lysosomal ceramide plays a critical role in phenotype change and sEV release in SMCs, which may contribute to the arterial stiffness during the development of AMC.

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Section: Methodsmentioning

confidence: 99%

Medial calcification in the arterial wall of smooth muscle cell‐specific Smpd1 transgenic mice: A ceramide‐mediated vasculopathy

Bhat

Yuan

Cain

et al. 2019

J Cellular Molecular Medi

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“…However, prior treatments of podocyte with acid ceramidase inducer (genistein) or Asah1 CRISPR/cas9 activation plasmids were found to decrease d-ribose-induced ceramide accumulation, EVs release and IL-1β secretion due to reduced interactions of MVBs with lysosome. These results indicated that d-ribose stimulation lead to the release of inflammasome-derived products such as IL-1β via EVs, in which lysosomal sphingolipid-mediated regulation of lysosome function plays an important role 65 . To our knowledge, the present study provide the first experimental evidence demonstrating the critical role of lysosomal Ac in the regulation of sEV secretion from SMCs and in the development of AMC.…”

Section: Discussionmentioning

confidence: 86%

Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice

Bhat

Yuan

et al. 2020

Sci Rep

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Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (Asah1 fl/fl /SM cre) were used to demonstrate the role of lysosomal ceramide signaling pathway in AMC. Asah1 fl/fl /SM cre mice were found to have more severe AMC in both aorta and coronary arteries compared to their littermates (Asah1 fl/fl /SM wt and WT/WT mice) after receiving a high dose vitamin D. These mice also had pronounced upregulation of osteopontin and RUNX2 (osteogenic markers), CD63, AnX2 (sEV markers) and ALP expression (mineralization marker) in the arterial media. In cultured coronary arterial smooth muscle cells (CASMCs) from Asah1 fl/fl /SM cre mice, high dose of P i led to a significantly increased calcium deposition, phenotypic change and sEV secretion compared to WT CASMCs, which was associated with reduced lysosome-multivesicular body (MVB) interaction. Also, GW4869, sEV release inhibitor decreased sEV secretion and calcification in these cells. Lysosomal transient receptor potential mucolipin 1 (TRPML1) channels regulating lysosome interaction with MVBs were found remarkably inhibited in Asah1 fl/fl /SM cre CASMCs as shown by GCaMP3 Ca 2+ imaging and Port-a-Patch patch clamping of lysosomes. Lysosomal Ac in SMCs controls sEV release by regulating lysosomal TRPML1 channel activity and lysosome-MVB interaction, which importantly contributes to phenotypic transition and AMC. Arterial calcification involves the accumulation or deposition of apatite calcium salts within the vascular wall that has been associated with aging, atherosclerosis, diabetes mellitus and chronic kidney disease (CKD) 1. Anatomically, arterial calcification is classified into intimal and medial calcification 2. The intimal calcification often causes occlusion of the arteries, which is characterized by accumulation of lipids, inflammation, and fibrosis observed as irregular scattered deposits in the atherosclerotic plaques 3. The arterial medial calcification (AMC) increases arterial stiffness, which is detected as continuous linear hydroxyapatite deposits in the absence of inflammatory cells along the internal elastic lamina. It is frequently observed in the elderly people or in patients with diabetic mellitus and chronic renal failure 4,5. Literature cites that under normal physiological conditions, spontaneous accumulation of calcium and phosphate levels doesn't induce arterial calcification because minerals (Ca/P i) are tightly balanced in the vasculature 6,7. Increased intracellular phosphate levels in vascular smooth muscle cells (VSMCs) directly drive their osteogenic differentiation and mineralization, inducing expression of osteogenic markers like RUNX2 and osteopontin 8,9 , associated with secretion of matrix vesicles as primary nucleation sites for calcification 7,9. Several studies including ex vivo human samples and ...

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“…A recent study in our lab has demonstrated that D-ribose induces formation and activation of NLRP3 inflammasome in podocytes via AGE/RAGE signaling pathway, which may contribute to the initiation of podocyte injury and glomerular damage during diabetes [138]. After NLRP3 inflammasome is activated, sphingolipid-mediated regulation of lysosome function significantly affects the release of inflammasome-derived products into extracellular space via exosomes [139]. Both inhibition of lysosomal ASM and activation of lysosomal AC attenuated inflammatory exosome release through enhancement of lysosome-dependent degradation of MVBs [139].…”

Section: Diabetic Nephropathymentioning

confidence: 98%

“…After NLRP3 inflammasome is activated, sphingolipid-mediated regulation of lysosome function significantly affects the release of inflammasome-derived products into extracellular space via exosomes [139]. Both inhibition of lysosomal ASM and activation of lysosomal AC attenuated inflammatory exosome release through enhancement of lysosome-dependent degradation of MVBs [139]. In conclusion, lysosomal sphingolipid metabolism as a regulator of inflammatory exosome release may be a novel target for the development of therapeutic strategy for prevention and treatment of DN.…”

Section: Diabetic Nephropathymentioning

confidence: 99%

“…Furthermore, the biogenesis, degradation, and release of exosomes could be a novel target for the development of therapies against CKD. For example, D-ribose has been shown to induce NLRP3 inflammasome activation and inflammatory exosome release in podocytes both in vitro and in vivo [139]. In addition, TRPML1 channel-mediated Ca 2+ release has been demonstrated to control lysosome trafficking, MVB degradation, and exosome release in murine podocytes [173].…”

Section: Therapeutic Potential Of Chronic Glomerular Diseases By Restmentioning

confidence: 99%

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Podocyte Lysosome Dysfunction in Chronic Glomerular Diseases

Kidd

2020

IJMS

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Podocytes are visceral epithelial cells covering the outer surface of glomerular capillaries in the kidney. Blood is filtered through the slit diaphragm of podocytes to form urine. The functional and structural integrity of podocytes is essential for the normal function of the kidney. As a membrane-bound organelle, lysosomes are responsible for the degradation of molecules via hydrolytic enzymes. In addition to its degradative properties, recent studies have revealed that lysosomes may serve as a platform mediating cellular signaling in different types of cells. In the last decade, increasing evidence has revealed that the normal function of the lysosome is important for the maintenance of podocyte homeostasis. Podocytes have no ability to proliferate under most pathological conditions; therefore, lysosome-dependent autophagic flux is critical for podocyte survival. In addition, new insights into the pathogenic role of lysosome and associated signaling in podocyte injury and chronic kidney disease have recently emerged. Targeting lysosomal functions or signaling pathways are considered potential therapeutic strategies for some chronic glomerular diseases. This review briefly summarizes current evidence demonstrating the regulation of lysosomal function and signaling mechanisms as well as the canonical and noncanonical roles of podocyte lysosome dysfunction in the development of chronic glomerular diseases and associated therapeutic strategies.

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Lysosomal regulation of extracellular vesicle excretion during d-ribose-induced NLRP3 inflammasome activation in podocytes

Cited by 40 publications

References 51 publications

Medial calcification in the arterial wall of smooth muscle cell‐specific Smpd1 transgenic mice: A ceramide‐mediated vasculopathy

Medial calcification in the arterial wall of smooth muscle cell‐specific Smpd1 transgenic mice: A ceramide‐mediated vasculopathy

Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice

Podocyte Lysosome Dysfunction in Chronic Glomerular Diseases

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