Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion

Zhuang, Aowen; Yap, Felicia Y. T.; McCarthy, Domenica A.; Leung, Christopher; Sourris, Karly C.; Penfold, Sally A.; Thallas‐Bonke, Vicki; Coughlan, Melinda T.; Schulz, Benjamin L.; Forbes, Josephine M.

doi:10.1038/s41598-019-50221-0

Cited by 5 publications

(3 citation statements)

References 57 publications

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“…One of this receptor is AGER1, also known as OCT48, which lowers AGEs and facilitates its clearance into urine ( Vlassara et al, 2009b ; Uribarri et al, 2011 ) and is known as an anti-inflammatory AGE receptor ( Lu et al, 2004 ); it is downregulated in many autoimmune diseases such as CDK and diabetes ( Stinghen et al, 2016 ). Although AGER1 receptor’s over-expression clears AGE burden, it leads to tubulointerstitial damage and fibrosis ( Zhuang et al, 2019 ). Similarly, when overexpressed in mice podocytes, glomerulosclerosis and podocyte injury result despite AGE clearance ( Zhuang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

RAGE is a critical factor of sex-based differences in age-induced kidney damage

Bajwa

Luebbe

et al. 2023

Front. Physiol.

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Introduction: Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE). RAGE is a transmembrane protein that belongs to the immunoglobulin superfamily and has the ability to interact with multiple pro-inflammatory/pro-oxidative ligands. The role of RAGE in aging kidneys has not been fully characterized, especially for sex-based differences.Methods: Therefore, we analyzed constitutive RAGE knockout (KO) mice in an age- and sex-dependent manner. Paraffin-embedded kidney sections were used for histological analysis and protein expression of fibrosis and damage markers. RNA expression analysis from the kidney cortex was done by qPCR for AGE receptors, kidney damage, and early inflammation/fibrosis factors. FACS analysis was used for immune cell profiling of the kidneys.Results: Histological analysis revealed enhanced infiltration of immune cells (positive for B220) in aged (>70 weeks old) KO mice in both sexes. FACS analysis revealed a similar pattern of enhanced B-1a cells in aged KO mice. There was an age-based increase in pro-fibrotic and pro-inflammatory markers (IL-6, TNF, TGF-β1, and SNAIL1) in KO male mice that presumably contributed to renal fibrosis and renal damage (glomerular and tubular). In fact, in KO mice, there was an age-dependent increase in renal damage (assessed by NGAL and KIM1) that was accompanied by increased fibrosis (assessed by CTGF). This effect was more pronounced in male KO mice than in the female KO mice. In contrast to the KO animals, no significant increase in damage markers was detectable in wild-type animals at the age examined (>70 weeks old). Moreover, there is an age-based increase in AGEs and scavenger receptor MSR-A2 in the kidneys.Discussion: Our data suggest that the loss of the clearance receptor RAGE in male animals further accelerates age-dependent renal damage; this could be in part due to an increase in AGEs load during aging and the absence of protective female hormones. By contrast, in females, RAGE expression seems to play only a minor role when compared to tissue pathology.

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Section: Discussionmentioning

confidence: 99%

RAGE is a critical factor of sex-based differences in age-induced kidney damage

Bajwa

Luebbe

et al. 2023

Front. Physiol.

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“…Many factors can lead to renal fibrosis in DKD, such as AGEs, mitochondrial dysfunction, autophagy dysfunction, activation of inflammatory pathway and so on (37)(38)(39). AGEs is considered to be an important factor in the process of DKD renal fibrosis, which can promote the process by stimulating the secretion of oxygen free radicals, cytokines, chemokines, adhesion molecules, TGF-β, CTGF, and other mediators (15,40). Therefore, the current study is conducted to reveal the mechanism of renal tubulointerstitial fibrosis induced by AGEs with the conclusion pronouncing that AGEs reduce the fibrosis progression in DKD through the JMJD1A/NR4A1 axis.…”

Section: Discussionmentioning

confidence: 99%

JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2

et al. 2022

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Diabetic kidney disease (DKD) is one of the most serious complications of diabetic patients. Advanced glycation end products (AGEs) induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (HK-2), resulting in renal tubulointerstitial fibrosis. However, the underlying epigenetic mechanisms remain to be further investigated. In this work, we investigated the functional role of JMJD1A involved in DKD progression. The molecular mechanism study was performed in AGEs-induced HK-2 cells by gene expression analysis, RNA sequencing (RNA-seq), and JMJD1A lentiviral knockdown and overexpression particle transfection. The results showed that AGEs could upregulate JMJD1A, and the expressions of related fibrotic factor were also increased. At the same time, in the DKD animal model induced by unilateral nephrectomy plus streptozotocin (STZ), IHC immunohistochemical staining showed that compared with the control group, the expressions of JMJD1A, FN, and COL1 in the model group were all increased, masson staining results also show that the model group has typical fibrotic changes. This is consistent with the results of our in vitro experiments. In order to determine the downstream pathway, we screened out JMJD1A downstream transcription factors by RNA-seq. Further analysis showed that JMJD1A overexpression could accelerate the progression of AGEs-induced renal fibrosis by reducing the expression of NR4A1 in HK-2 cells. Meanwhile, NR4A1 inhibitor can promote the expression of fibrosis-related factors such as VIM, a-SMA in HK-2 cells, and aggravate the process of fibrosis. Taken together, JMJD1A/NR4A1 signaling can regulate the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2.

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“…In addition, oral administration of mannose suppressed the immunopathology in models of autoimmune diabetes and airway inflammation [12]. However, high dosage of mannose could cause injury towards the kidneys [13]. Furthermore, the scientific evidence on the cell viability pattern of the normal and cancer cell lines that were treated with mannose is insufficient.…”

Section: Introductionmentioning

confidence: 99%

A high mannose concentration is well tolerated by colorectal adenocarcinoma and melanoma cells but toxic to normal human gingival fibroblast: an in vitro investigation

Mazlan

Isa

Ibrahim

2020

Egypt J Med Hum Genet

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Background The primary cause of cancer is gene mutation which allows the growth of abnormal and damaged cells. Nutrition is one of the key factors that either increases or decreases the risk of cancer. Mannose has been found in many fruits such as oranges, apples and berries. Mannose has been linked to increase the risk factors or potential therapeutic for cancers. However, insufficient information is available on the effects of high mannose concentration on the normal and cancer cell lines. This study aimed to evaluate the viability patterns of human cancer and normal cell lines treated with mannose. Human gingival fibroblast (HGF), skin malignant melanoma (A375) and colorectal adenocarcinoma (HT29) cell lines were cultured and treated with additional mannose in three respective concentrations: 1 mg/ml, 5 mg/ml and 10 mg/ml. Then, cell viability was measured using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)-assay. Results The HGF cells’ percentage pattern of viability showed a rapid decline of nearly 95% on the third day of treatment. A375 cells were able to survive in high mannose condition as the cell viability percentage was at the highest value on Day 5. Meanwhile, HT29 cells showed declining cell viability pattern when treated with mannose. The data exhibited significance; the p value was less than 0.001. Conclusions High mannose concentration can be toxic to HGF. In addition, A375 is adaptive to mannose at all concentrations in which it shares the same pattern with the untreated group. However, the cell viability pattern for HT29 cell is declining.

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Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion

Cited by 5 publications

References 57 publications

RAGE is a critical factor of sex-based differences in age-induced kidney damage

RAGE is a critical factor of sex-based differences in age-induced kidney damage

JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2

A high mannose concentration is well tolerated by colorectal adenocarcinoma and melanoma cells but toxic to normal human gingival fibroblast: an in vitro investigation

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