Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response
Diabetic nephropathy is increasingly recognized as a major contributor to kidney failure in patients with obesity and type 2 diabetes. This study was designed to identify the molecular mediators of kidney injury associated with metabolic syndrome with or without hyperglycemia. We compared renal gene...
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doaj-fcaf8a41dbac45eb834c70b8eef633332020-11-25T01:20:41ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-07-012014340610.3390/ijms20143406ijms20143406Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory ResponseXueying Zhao0Xiaoming Chen1Yuanyuan Zhang2Jasmine George3Alyssa Cobbs4Guoshen Wang5Lingyun Li6Nerimiah Emmett7Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADepartment of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USADiabetic nephropathy is increasingly recognized as a major contributor to kidney failure in patients with obesity and type 2 diabetes. This study was designed to identify the molecular mediators of kidney injury associated with metabolic syndrome with or without hyperglycemia. We compared renal gene expression profiles in Zucker lean (ZL), Zucker obese (ZO), and Zucker diabetic (ZD) rats using cDNA microarray with quantitative verification of selected transcripts by real-time PCR. Compared to the 20-week-old ZL control (glucose: 110 ± 8 mg/dL), both prediabetic ZO (glucose: 157 ± 11 mg/dL) and diabetic ZD (glucose: 481 ± 37 mg/dL) rats displayed hyperlipidemia and kidney injury with a high degree of proteinuria. cDNA microarray identified 25 inflammation and injury-related transcriptomes whose expression levels were similarly increased in ZO and ZD kidneys. Among them, kidney injury molecule-1 (KIM-1) was found to be the most highly upregulated in both ZO and ZD kidneys. Immunofluorescence staining of kidney sections revealed a strong correlation between lipid overload and KIM-1 upregulation in proximal tubules of ZO and ZD rats. In cultured primary renal tubular epithelial cells (TECs), administration of saturated fatty acid palmitate resulted in an upregulation of KIM-1, osteopontin, and CD44, which was greatly attenuated by U0126, an inhibitor of extracellular signal-regulated kinase (ERK)1/2. Moreover, knockdown of KIM-1 by siRNA interference inhibited palmitate-induced cleaved caspase-3, osteopontin, and CD44 proteins in primary TECs. Our results indicate that KIM-1 expression is upregulated in renal lipotoxicity and may play an important role in fatty acid-induced inflammation and tubular cell damage in obesity and diabetic kidney disease.https://www.mdpi.com/1422-0067/20/14/3406lipotoxicitymetabolic syndromeinflammationnephropathy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xueying Zhao Xiaoming Chen Yuanyuan Zhang Jasmine George Alyssa Cobbs Guoshen Wang Lingyun Li Nerimiah Emmett |
spellingShingle |
Xueying Zhao Xiaoming Chen Yuanyuan Zhang Jasmine George Alyssa Cobbs Guoshen Wang Lingyun Li Nerimiah Emmett Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response International Journal of Molecular Sciences lipotoxicity metabolic syndrome inflammation nephropathy |
author_facet |
Xueying Zhao Xiaoming Chen Yuanyuan Zhang Jasmine George Alyssa Cobbs Guoshen Wang Lingyun Li Nerimiah Emmett |
author_sort |
Xueying Zhao |
title |
Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response |
title_short |
Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response |
title_full |
Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response |
title_fullStr |
Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response |
title_full_unstemmed |
Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response |
title_sort |
kidney injury molecule-1 is upregulated in renal lipotoxicity and mediates palmitate-induced tubular cell injury and inflammatory response |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-07-01 |
description |
Diabetic nephropathy is increasingly recognized as a major contributor to kidney failure in patients with obesity and type 2 diabetes. This study was designed to identify the molecular mediators of kidney injury associated with metabolic syndrome with or without hyperglycemia. We compared renal gene expression profiles in Zucker lean (ZL), Zucker obese (ZO), and Zucker diabetic (ZD) rats using cDNA microarray with quantitative verification of selected transcripts by real-time PCR. Compared to the 20-week-old ZL control (glucose: 110 ± 8 mg/dL), both prediabetic ZO (glucose: 157 ± 11 mg/dL) and diabetic ZD (glucose: 481 ± 37 mg/dL) rats displayed hyperlipidemia and kidney injury with a high degree of proteinuria. cDNA microarray identified 25 inflammation and injury-related transcriptomes whose expression levels were similarly increased in ZO and ZD kidneys. Among them, kidney injury molecule-1 (KIM-1) was found to be the most highly upregulated in both ZO and ZD kidneys. Immunofluorescence staining of kidney sections revealed a strong correlation between lipid overload and KIM-1 upregulation in proximal tubules of ZO and ZD rats. In cultured primary renal tubular epithelial cells (TECs), administration of saturated fatty acid palmitate resulted in an upregulation of KIM-1, osteopontin, and CD44, which was greatly attenuated by U0126, an inhibitor of extracellular signal-regulated kinase (ERK)1/2. Moreover, knockdown of KIM-1 by siRNA interference inhibited palmitate-induced cleaved caspase-3, osteopontin, and CD44 proteins in primary TECs. Our results indicate that KIM-1 expression is upregulated in renal lipotoxicity and may play an important role in fatty acid-induced inflammation and tubular cell damage in obesity and diabetic kidney disease. |
topic |
lipotoxicity metabolic syndrome inflammation nephropathy |
url |
https://www.mdpi.com/1422-0067/20/14/3406 |
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