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Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis.

Simon N, Hertig A - Front Med (Lausanne) (2015)

Bottom Line: The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids.When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over.In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.

View Article: PubMed Central - PubMed

Affiliation: IMSERM UMR_S1155, Rare and Common Kidney Diseases, Remodeling and Tissue Repair, Hôpital Tenon , Paris , France.

ABSTRACT
Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.

No MeSH data available.


Related in: MedlinePlus

Transforming growth factor-β1/SMAD3 mediated-regulation of FAO. TGF-β1 is up-regulated after acute kidney injury, which activates SMAD3, which in turn can bind to an intronic region of the PPARGC1A gene. SMAD3 binding overlaps with the active enhancer histone tail modification H3K4me1 of this sequence, resulting in the blocking of the progression transcription machinery. In addition, this region is also annotated as an active enhancer in human kidney PTC (14). SMAD3 can also target PPAR-α, the other key regulator gene of FAO, through microRNA (miR-21) overexpression. miR-21 silences PPAR-α by recognition of an octamer sequence complementary to miR-21 seed region in the 3′UTR of PPAR-α mRNA (32). These two mechanisms cooperate in the acquisition of a pro-fibrotic phenotype. Abbreviations: PPAR-α, peroxisome proliferator activated receptor-alpha; PPARGC1A, PPAR-γ co-activator-1a; RISC, RNA-induced silencing complex; TGF-β1, transforming growth factor β1.
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Figure 2: Transforming growth factor-β1/SMAD3 mediated-regulation of FAO. TGF-β1 is up-regulated after acute kidney injury, which activates SMAD3, which in turn can bind to an intronic region of the PPARGC1A gene. SMAD3 binding overlaps with the active enhancer histone tail modification H3K4me1 of this sequence, resulting in the blocking of the progression transcription machinery. In addition, this region is also annotated as an active enhancer in human kidney PTC (14). SMAD3 can also target PPAR-α, the other key regulator gene of FAO, through microRNA (miR-21) overexpression. miR-21 silences PPAR-α by recognition of an octamer sequence complementary to miR-21 seed region in the 3′UTR of PPAR-α mRNA (32). These two mechanisms cooperate in the acquisition of a pro-fibrotic phenotype. Abbreviations: PPAR-α, peroxisome proliferator activated receptor-alpha; PPARGC1A, PPAR-γ co-activator-1a; RISC, RNA-induced silencing complex; TGF-β1, transforming growth factor β1.

Mentions: Peroxisome proliferator activated receptor-alpha (PPAR-α) is a transcription factor predominantly expressed in metabolically very active tissues, such as renal PTC, and has been shown to control FAO. In homeostasis, endogenous levels of FA act directly on PPAR-α as natural activators of this ligand-activated receptor superfamily member. PPAR-α increases the transcription of genes encoding FAO enzymes, and also acts upstream by stimulating cellular FA uptake through the modulation of the FA translocase CD36 (28). Conversely, during AKI, PPAR-α mRNA, and its DNA binding activity were found to decrease, as was the availability of its tissue specific co-activator PPAR-γ co-activator-1a (PPARGC1A) (29–31). Kang et al. have reported that transforming growth factor β1 (TGF-β1), a major player in kidney fibrosis, and a master inducer of EMT, can inhibit PPAR-α and PPARGC1A, key transcription factors of FAO genes. It logically results in a down-regulation of CPT-1 and triglyceride overload. How TGF-β1 suppresses PPAR-α, and PPARGC1A seems to be epigenetically regulated. MicroRNA-21 (miR-21), a downstream target of Smad3 (32), is able to silence PPAR-α (33). Strikingly, anti-miR-21 failed to suppress renal fibrosis in PPAR-α−/− mice, incidentally underlining the major role of PPAR-α/FAO in the process of renal fibrogenesis. In addition, chromatin immunoprecipitation (CHiP) studies revealed that Smad3 can bind to an intronic area of the PPARGC1A promoter, at a position where the DNA is enriched in the histone mark H3K4me1 (read: mono-methylation of lysine 4 in histone 3, a mark usually associated with activation of transcription). By overlapping with this region, Smad3 could thus impede epigenetic activation of PPARGC1A (14) (Figure 2).


Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis.

Simon N, Hertig A - Front Med (Lausanne) (2015)

Transforming growth factor-β1/SMAD3 mediated-regulation of FAO. TGF-β1 is up-regulated after acute kidney injury, which activates SMAD3, which in turn can bind to an intronic region of the PPARGC1A gene. SMAD3 binding overlaps with the active enhancer histone tail modification H3K4me1 of this sequence, resulting in the blocking of the progression transcription machinery. In addition, this region is also annotated as an active enhancer in human kidney PTC (14). SMAD3 can also target PPAR-α, the other key regulator gene of FAO, through microRNA (miR-21) overexpression. miR-21 silences PPAR-α by recognition of an octamer sequence complementary to miR-21 seed region in the 3′UTR of PPAR-α mRNA (32). These two mechanisms cooperate in the acquisition of a pro-fibrotic phenotype. Abbreviations: PPAR-α, peroxisome proliferator activated receptor-alpha; PPARGC1A, PPAR-γ co-activator-1a; RISC, RNA-induced silencing complex; TGF-β1, transforming growth factor β1.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4525064&req=5

Figure 2: Transforming growth factor-β1/SMAD3 mediated-regulation of FAO. TGF-β1 is up-regulated after acute kidney injury, which activates SMAD3, which in turn can bind to an intronic region of the PPARGC1A gene. SMAD3 binding overlaps with the active enhancer histone tail modification H3K4me1 of this sequence, resulting in the blocking of the progression transcription machinery. In addition, this region is also annotated as an active enhancer in human kidney PTC (14). SMAD3 can also target PPAR-α, the other key regulator gene of FAO, through microRNA (miR-21) overexpression. miR-21 silences PPAR-α by recognition of an octamer sequence complementary to miR-21 seed region in the 3′UTR of PPAR-α mRNA (32). These two mechanisms cooperate in the acquisition of a pro-fibrotic phenotype. Abbreviations: PPAR-α, peroxisome proliferator activated receptor-alpha; PPARGC1A, PPAR-γ co-activator-1a; RISC, RNA-induced silencing complex; TGF-β1, transforming growth factor β1.
Mentions: Peroxisome proliferator activated receptor-alpha (PPAR-α) is a transcription factor predominantly expressed in metabolically very active tissues, such as renal PTC, and has been shown to control FAO. In homeostasis, endogenous levels of FA act directly on PPAR-α as natural activators of this ligand-activated receptor superfamily member. PPAR-α increases the transcription of genes encoding FAO enzymes, and also acts upstream by stimulating cellular FA uptake through the modulation of the FA translocase CD36 (28). Conversely, during AKI, PPAR-α mRNA, and its DNA binding activity were found to decrease, as was the availability of its tissue specific co-activator PPAR-γ co-activator-1a (PPARGC1A) (29–31). Kang et al. have reported that transforming growth factor β1 (TGF-β1), a major player in kidney fibrosis, and a master inducer of EMT, can inhibit PPAR-α and PPARGC1A, key transcription factors of FAO genes. It logically results in a down-regulation of CPT-1 and triglyceride overload. How TGF-β1 suppresses PPAR-α, and PPARGC1A seems to be epigenetically regulated. MicroRNA-21 (miR-21), a downstream target of Smad3 (32), is able to silence PPAR-α (33). Strikingly, anti-miR-21 failed to suppress renal fibrosis in PPAR-α−/− mice, incidentally underlining the major role of PPAR-α/FAO in the process of renal fibrogenesis. In addition, chromatin immunoprecipitation (CHiP) studies revealed that Smad3 can bind to an intronic area of the PPARGC1A promoter, at a position where the DNA is enriched in the histone mark H3K4me1 (read: mono-methylation of lysine 4 in histone 3, a mark usually associated with activation of transcription). By overlapping with this region, Smad3 could thus impede epigenetic activation of PPARGC1A (14) (Figure 2).

Bottom Line: The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids.When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over.In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.

View Article: PubMed Central - PubMed

Affiliation: IMSERM UMR_S1155, Rare and Common Kidney Diseases, Remodeling and Tissue Repair, Hôpital Tenon , Paris , France.

ABSTRACT
Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.

No MeSH data available.


Related in: MedlinePlus