Amelioration of Diabetic Nephropathy Using a Retinoic Acid Receptor<i>β</i>2 Agonist

Trasino, Steven E.; Tang, Xiao‐Han; Shevchuk, Maria M.; Choi, Mary E.; Gudas, Lorraine J.

doi:10.1124/jpet.118.249375

Cited by 21 publications

(13 citation statements)

References 105 publications

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“…However, recent data suggest that podocytes can accumulate lipid droplets, and that this process is associated with activation of the inflammasome and is involved in the pathogenesis of glomerulopathy associated with T2DM and obesity 24,49‐51 . Consistently with decreased retinol bioavailability in pericytes carrying the PNPLA3 I148M variant, 43‐45 it has been reported that a highly selective agonist for retinoic acid receptor β2 (ie AC261) was able to ameliorate diabetic nephropathy in an experimental mouse model 52 . However, further mechanistic studies are needed to examine the role of PNPLA3 and the impact of the I148M variant on retinol and lipid metabolism in the kidney, as well as on the inflammatory and fibrogenic responses to injury in renal podocytes.…”

Section: Discussionmentioning

confidence: 98%

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

Mantovani

Taliento

Zusi

et al. 2020

Liver International

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Background and Aims:Emerging evidence suggests an association between patatinlike phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods:We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73 m 2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results:In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m 2 , P = .0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P = .028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P < .0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P = .008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. Conclusions:The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes. | 1131 MANTOVANI eT Al.

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Section: Discussionmentioning

confidence: 98%

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

Mantovani

Taliento

Zusi

et al. 2020

Liver International

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“…RARB encodes the retinoic acid receptor (RAR) beta, and nuclear receptors, including retinoic acid receptor (RAR), have been proposed to play a protective role in podocytes [ 61 ]. Using an RAR ß2 agonist improved podocyte effacement in a diabetic nephropathy model [ 62 ]. In our study, the downregulated expression of RAR during IL-4 treatment supported this finding.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome

Lee

et al. 2021

JCM

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Interleukin-4 (IL-4) expression is implicated in the pathogenesis of nephrotic syndrome (NS). This study aimed to investigate the changes in the transcriptomes of human podocytes induced by IL-4 treatment and to analyze whether these changes could be affected by simultaneous steroid treatment. Three groups of human podocytes were treated with control, IL-4, and IL-4 plus dexamethasone (DEX), respectively. We performed whole-transcriptome sequencing to identify differentially expressed genes (DEGs) between the groups. We investigated relevant biological pathways using Gene Ontology (GO) enrichment analyses. We also attempted to compare and validate the DEGs with the genes listed in PodNet, a literature-based database on mouse podocyte genes. A total of 176 genes were differentially expressed among the three groups. GO analyses showed that pathways related to cytoskeleton organization and cell signaling were significantly enriched. Among them, 24 genes were listed in PodNet, and 12 of them were previously reported to be associated with IL-4-induced changes in human podocytes. Of the 12 genes, the expression levels of BMP4, RARB, and PLCE1 were reversed when podocytes were simultaneously treated with DEX. In conclusion, this study explored changes in the transcriptome profiles of human podocytes treated with IL-4. Few genes were reported in previous studies and were previously validated in experiments with human podocytes. We speculate that IL-4 may exert pathogenic effects on the transcriptome of human podocytes, and a few genes may be involved in the pathogenesis.

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“…Hsieh et al () indicated that retinoid X receptor γ may be involved in the pathogenesis of DN. Trasino, Tang, Shevchuk, Choi, & Gudas () demonstrated that AC261066, a retinoic acid receptor β2 agonist, could inhibit the progression of DN. Besides, the dysfunction in fatty acid oxidation was implicated to have a role in lipotoxicity in DN (Murea et al, ).…”

Section: Discussionmentioning

confidence: 99%

Multiple‐microarray analysis for identification of hub genes involved in tubulointerstial injury in diabetic nephropathy

Liu

Yang

et al. 2019

Journal Cellular Physiology

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Diabetic nephropathy (DN) is a primary cause of renal failure. However, studies providing renal gene expression profiles of diabetic tubulointerstitial injury are scarce and its molecular mechanisms still await clarification. To identify vital genes involved in the diabetic tubulointerstitial injury, three microarray data sets from gene expression omnibus (GEO) were downloaded. A total of 127 differentially expressed genes (DEGs) were identified by limma package. Gene set enrichment analysis (GSEA) plots showed that sister chromatid cohesion was the most significant enriched gene set positively correlated with the DN group while retinoid X receptor binding was the most significant enriched gene set positively correlated with the control group. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included extracellular matrix organization, extracellular space, extracellular matrix structural constituent, and Staphylococcus aureus infection. Twenty hub genes from three significant modules were ascertained by Cytoscape. Correlation analysis and subgroup analysis between hub genes and clinical features of DN showed that ALB, ANXA1, APOH, C3, CCL19, COL1A2, COL3A1, COL4A1, COL6A3, CXCL6, DCN, EGF, HRG, KNG1, LUM, SERPINA3, SPARC, SRGN, and TIMP1 may involve in diabetic tubulointerstitial injury. ConnectivityMap analysis indicated the most significant three compounds are 5182598, thapsigargin and 5224221. In conclusion, this study may provide new insights into the molecular mechanisms underlying diabetic tubulointerstitial injury as well as potential targets for diagnosis and therapeutics of DN.

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Amelioration of Diabetic Nephropathy Using a Retinoic Acid Receptorβ2 Agonist

Abstract: 246Introduction: 846 (including references)

Cited by 21 publications

References 105 publications

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

PNPLA3I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings

The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome

Multiple‐microarray analysis for identification of hub genes involved in tubulointerstial injury in diabetic nephropathy

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