Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response

Zhao, Xueying; Chen, Xiaoming; Zhang, Yuanyuan; George, Jasmine; Cobbs, Alyssa; Wang, Guoshen; Li, Lingyun; Emmett, Nerimiah

doi:10.3390/ijms20143406

Cited by 30 publications

(22 citation statements)

References 40 publications

(65 reference statements)

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“…These findings support the significance of CD44 and osteopontin expression in fatty acid-induced tubular cell damage in DKD (40). We identified no studies directly connecting SHMT2 to DKD.…”

Section: Discussionsupporting

confidence: 81%

Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease

Collins

Eadon

Cheng

et al. 2021

Preprint

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Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.

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Section: Discussionsupporting

confidence: 81%

Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease

Collins

Eadon

Cheng

et al. 2021

Preprint

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“…Histopathologically, the injury of renal epithelial cells by CDDP began to be seen clearly on day 3, and the injury lesions became greater in severity on days 5 and 7; the damaged renal tubules were characterized by swelling, necrosis and desquamation of epithelial cells [ 19 , 20 ]. Additionally, mRNA expression of KIM-1, a marker of renal injury [ 27 ], began to significantly increase on day 5, with the continuous expression until day 15; KIM-1 immuno-expression was seen mainly in abnormally regenerating epithelial cells of damaged tubules. Collectively, CD68 + macrophages appearing mainly at the mid-stage may participate in the progressive renal injury which was caused initially by CDDP.…”

Section: Discussionmentioning

confidence: 99%

Immunophenotypical Characterization of M1/M2 Macrophages and Lymphocytes in Cisplatin-Induced Rat Progressive Renal Fibrosis

Nakagawa

Karim

Izawa

et al. 2021

Cells

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Renal fibrosis is regarded as the common final pathway leading to chronic kidney diseases; macrophages and myofibroblasts play important roles in the development of fibrosis. F344 rats were injected once with cisplatin (CDDP; 6 mg/kg BW) for renal lesions. Here, immunophenotypical characteristics of macrophages and lymphocytes in CDDP-induced rat renal lesions were investigated histopathologically; the CDDP-induced renal lesions consisted of tissue damage at the early-stage, worsen the damage and commencement of interstitial fibrosis at the mid-stage, and progressive fibrosis at the late stage; the KIM-1 expression and α-SMA+ myofibroblast area reflected renal tubular damage/abnormal regeneration and renal interstitial fibrosis, respectively. CD68+ M1 macrophages began to increase at the mid-stage, with increased mRNA expressions of M1-related cytokines (INF-γ, TNF-α and IL-6), and then slightly decreased at the late-stage. CD163+ M2 macrophages showed a gradually increased number at the mid- and late-stages, accompanied by increased TGF-β1 mRNA expression (a fibrogenic factor). Double immunofluorescence using fibrotic samples at the late-stage revealed that 62.0–78.0% of CD68+ M1 macrophages co-expressed CD163, indicating that M1/M2 macrophages may contribute to progressive renal fibrosis in cooperation; further, MHC class II-expressing macrophages had a tendency towards M1 polarization, whereas CD204-expressing macrophages towards M2 polarization. In addition, CD4+ and CD8+ T cells were increased at the late-stage. Collectively, progressive renal interstitial fibrosis may be developed by complicated mechanisms that arose via interaction of M1/M2 macrophages (inflammatory for M1 and anti-inflammatory for M2) and T cells reacting to CD4 (for helper) and CD8 (for cytotoxicity). This study would provide some information on the pathogenesis of renal fibrosis based on inflammatory cells.

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“…This hypothesis is supported by the evident increase, both in vivo and in vitro , in the phosphorylation of ERK and JNK pathways in our study. Activation of MAPK ERK1/2 and JNK pathways is known to be involved in the development of insulin resistance and in the regulation of mitochondrial activity ( Guebre-Egziabher et al, 2013 ; Wortzel and Seger, 2011 ; Zeke et al, 2016 ; Zhao et al, 2019 ). In our model, we failed to observe an increase in the phosphorylation of SMAD2/3; however, Smad7 mRNA levels were significantly decreased, suggesting that there is a lack of inhibition of this pathway.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney

Escasany

Lanzón

García-Carrasco

et al. 2021

Disease Models &Amp; Mechanisms

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Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor β (TGFβ) is a key player in the development of fibrosis. However, of the three known TGFβ isoforms, only TGFβ1 has an established role in fibrosis, and the pathophysiological relevance of TGFβ2 and TGFβ3 is unknown. Because Tgfβ3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfβ3-knockout mice (Tgfβ3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfβ3+/- mice exhibited incipient renal fibrosis with epithelial-to-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis showed toxic species such as diacylglycerides and ceramides in Tgfβ3+/- mice, and dysregulated mitochondrial metabolism. Kidney of Tgfβ3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study shows that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1.

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Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response

Cited by 30 publications

References 40 publications

Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease

Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease

Immunophenotypical Characterization of M1/M2 Macrophages and Lymphocytes in Cisplatin-Induced Rat Progressive Renal Fibrosis

Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney

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