scholarly journals MO431LIPIDOMIC ANALYSIS IN A NON-DIABETIC RAT MODEL WITH HYPERFILTRATION AND ALBUMINURIA REVEALS DYNAMIC CHANGES IN THE PROSTAGLANDIN E2 PATHWAY DURING ONSET OF ALBUMINURIA AS A POTENTIAL CAUSATIVE MECHANISM

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Eva Mangelsen ◽  
Michael Rothe ◽  
Juliane Bolbrinker ◽  
Aikaterini Kourpa ◽  
Daniela Panáková ◽  
...  

Abstract Background and Aims We recently identified prostaglandin reductase 2 (Ptgr2) and the prostaglandin E2 (PGE2) pathway as potential causative mechanism in the Munich Wistar Frömter (MWF) non-diabetic rat model of chronic kidney disease. MWF is characterized by early onset of spontaneous albuminuria during a critical time window between 4 and 8 weeks of age, that associates with hyperfiltration, due to low nephron number, and podocyte injury. Ptgr2 plays an important role in the prostaglandin metabolism, in which PGE2 is metabolized by 15-prostaglandin dehydrogenase (15-PGDH) to 15-keto-PGE2. The latter is terminally degraded by prostaglandin reductases (PTGRs) 1, 2, and 3 to 13,14-dihydro-15-keto-PGE2. Recently, we detected elevated glomerular levels of PGE2 and 15-keto-PGE2 in MWF compared to spontaneously hypertensive rats (SHR) with no albuminuria. The aim of the present study was to characterize in detail the renal PGE2 metabolic pathway in MWF by lipidomic analysis during the time window of albuminuria onset. Method Male MWF and SHR rats were studied at week 4 and 8, respectively; 24 h-urine was collected in metabolic cages. In addition, plasma and kidney tissues including kidney cortex and isolated glomeruli were obtained from anesthetized rats. Lipidomic analysis was done by liquid chromatography electrospray ionization tandem mass spectrometry. Statistical analysis was performed by unpaired, two-tailed Student’s t-test, or otherwise the Mann-Whitney test. Results Urinary PGE2 was significantly lower (p<0.01), while urinary 15-keto-PGE2 and 13,14-dihydro-15-keto PGE2 levels were significantly increased in MWF compared to SHR at week 4 (p<0.01, respectively). All three analytes were significantly decreased in urine of MWF with increased albuminuria at week 8 (p<0.05 vs. SHR). The urinary metabolic ratio of 15-keto-PGE2/13,14-dihydro-15-keto-PGE2 as a surrogate for PTGRs activities was significantly increased at week 4 (p<0.01), whereas it was significantly decreased in MWF vs. SHR at week 8 (p<0.05). Plasma levels of PGE2 and 13,14-dihydro-15-keto-PGE2 did not differ between strains at both time points, while 15-keto-PGE2 was below the detection limit. Glomerular levels of PGE2 and 15-keto-PGE2 were increased in MWF at week 4 and 8 (p<0.01, respectively). In contrast, 13,14-dihydro-15-keto-PGE2 was only significantly higher at week 4 compared to SHR (p<0.01). In isolated glomeruli, the metabolic ratios of PTGRs were similar between the strains at week 4, but significantly increased in MWF compared to SHR at week 8 (p<0.01, respectively). In kidney cortex, 15-keto-PGE2 and 13,14-dihydro-15-keto-PGE2 were increased in MWF at week 4 (p<0.05 and p<0.01, respectively), whereas PGE2 levels were comparable to SHR. No difference for cortical levels of PGE2 and its metabolites was observed at week 8. Conclusion This study provides the first insights into age-dependent dynamic changes in the PGE2 pathway that support potential causality for the onset of albuminuria in the setting of non-diabetic hyperfiltration due to low nephron number. Notably, the increased glomerular levels of PGE2 and its downstream metabolites in 4-week-old MWF point towards an early activation of this pathway, i.e. before albuminuria occurs. This finding corroborates the hypothesis that glomerular PGE2 signaling is relevant in the early stages of hyperfiltration and suggests this pathway as a target for future therapeutics to modify the manifestation and progression of renal disease.

2019 ◽  
Vol 19 (5) ◽  
pp. 622-631 ◽  
Author(s):  
Ya Liu ◽  
Jian Kang ◽  
Hong Gao ◽  
Xiyu Zhang ◽  
Jun Chao ◽  
...  

Background: Type 2 Diabetes Mellitus (T2DM) is a world-wide metabolic disease with no cure from drugs and treatment. In China, The Traditional Chinese Medicine (TCM) herbal formulations have been used to treat T2DM for centuries. Methods: In this study, we proposed a formula called ShenQi Compound (SQC), which has been used in clinical therapeutics in China for several years. We evaluated the effect of SQC in a spontaneous diabetic rat model (GK rats) by detecting a series of blood indicators and performing histological observations. Meanwhile, the gene microarray and RT-qPCR experiments were used to explore the molecular mechanism of SQC treatment. In addition, western medicine, sitagliptin was employed as a comparison. Results: The results indicated that SQC and sitagliptin could effectively improve the serum lipid (blood Total Cholesterol (TC) and blood Triglycerides (TG)), hormone levels (serum insulin (INS), Glucagon (GC) and Glucagon-Like Peptide-1 (GLP-1)), alleviated the inflammatory response (hypersensitive C-Reactive Protein (hsCRP)), blood glucose fluctuation (Mean Blood Glucose (MBG), standard deviation of blood glucose (SDBG) and Largest Amplitude of plasma Glucose Excursions (LAGE)), pancreatic tissue damage and vascular injury for T2DM. Compared with sitagliptin, SQC achieved a better effect on blood glucose fluctuation (p<0.01). Meanwhile, the gene microarray and RT-qPCR experiments indicated that SQC and sitagliptin may improve the T2DM through affecting the biological functions related to apoptosis and circadian rhythm. Moreover, SQC might be able to influence the mTOR signaling pathway by regulating Pik3r1, Ddit4 expression. Conclusion: All these results indicate that SQC is an effective therapeutic drug on T2DM. Notably, SQC presents an obvious blood glucose fluctuation-preventing ability, which might be derived from the regulation of the mTOR signaling pathway.


2015 ◽  
Vol 10 (2) ◽  
pp. 778-786 ◽  
Author(s):  
DE-HAI YIN ◽  
XIAO-CHUN LIANG ◽  
LI ZHAO ◽  
HONG ZHANG ◽  
QING SUN ◽  
...  

2013 ◽  
Vol 28 (5) ◽  
pp. 725 ◽  
Author(s):  
Sun-Ouck Kim ◽  
Hyun-Suk Lee ◽  
Kyuyoun Ahn ◽  
Kwangsung Park

2019 ◽  
Vol 16 (1) ◽  
pp. e1800365
Author(s):  
Regiane C. Duarte ◽  
Silvia H. Taleb-Contini ◽  
Paulo S. Pereira ◽  
Camila F. Oliveira ◽  
Carlos Eduardo S. Miranda ◽  
...  

2012 ◽  
Vol 265 (2) ◽  
pp. 209-220 ◽  
Author(s):  
Zivanit Ergaz ◽  
Dana Shoshani-Dror ◽  
Claire Guillemin ◽  
Meytal Neeman-azulay ◽  
Liza Fudim ◽  
...  

2015 ◽  
Vol 26 (8) ◽  
pp. 1768-1776 ◽  
Author(s):  
Yanmin Wang ◽  
Xiang Zhang ◽  
Mingwei Zhong ◽  
Teng Liu ◽  
Guangyong Zhang ◽  
...  

2018 ◽  
Vol 4 (2) ◽  
pp. 181-188 ◽  
Author(s):  
Medhat Ahmed El-Zainy ◽  
Ahmed Mahmoud Halawa ◽  
Fatma Adel Saad

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