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Retinol Dehydrogenase 10 Reduction Mediated Retinol Metabolism Disorder Promotes Diabetic Cardiomyopathy

ABSTRACT: Diabetic cardiomyopathy (DCM) is a primary myocardial injury induced by diabetes mellitus (DM) with a complex pathogenesis. In this study, we identified disordered cardiac retinol metabolism in T2DM mice and patients characterized by retinol (vitamin A, Rol) overload, all-trans retinoic acid (atRA) deficiency and retinoic acid receptors (RARs) reduction, and demonstrated that both cardiac Rol overload and atRA deficiency promote DCM by supplementing T2DM mice with Rol or atRA. Mechanically, by constructing cardiomyocyte-specific conditional RDH10-knockout mice and overexpressing RDH10 in T2DM mice via adeno-associated virus, we verified that the reduction in cardiac retinol dehydrogenase 10 (RDH10) is the initiating factor for cardiac retinol metabolism disorder and its resulting DCM. Additionally, lipotoxicity and ferroptosis contribute to the effect of retinol metabolism disorder on DCM. Based on these results, we suggest that the reduction of cardiac RDH10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying DCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE202418 | GEO | 2023/01/15

REPOSITORIES: GEO

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Project description:The circadian clock has been found to be associated with various diseases. We showed that 5/6 nephrectomy (5/6Nx) Clk/Clk mice, which show mutation in the gene encoding circadian locomotor output cycles (Clock) do not show aggravation of renal fibrosis because transforming growth factor-1 (Tgf-1) expression is not increased. In wild-type 5/6Nx kidneys, we found that retinoid, a metabolite of retinol, led to alteration of the expresion 24-h rhythm of Clock expression. Renal Tgf- 1 expression is activated by Clock and further aggravates renal dysfunction by causing fibrosis. We also showed that, in 5/6Nx mice fed a retinol-free diet, renal fibrosis and apoptosis are reduced, leading to a marked improvement in serum creatinine levels. Moreover, our study identified hepatic Cyp3a11 and Cyp26a1 as key retinol metabolism-related genes whose expression decreased in 5/6Nx mice. Our data indicated that the negative chain reaction of metabolic clock alteration in between the kidney and liver aggravates renal dysfunction. Differential gene expression between retinol (-) feeding and clock mutant in 5/6 nephrectomized mouse was measured on the kidney at 8 weeks after operation. Four-week-old male ICR mice (Charles River Japan, Inc., Yokohama, Japan) were housed in a light-controlled room (lights on from Zeitgeber time [ZT] 0 to ZT12) at 24 ± 1°C and 60 ± 10% humidity, with food and water available ad libitum. Mice were synchronized to the lighting conditions for 2 weeks before surgery. Male ICR mice (5 weeks old) were purchased from Charles River Japan, Inc. (Kanagawa, Japan). Clock mutant mice (C57BL/6J-ClockmlJt/J) were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). We placed them in the ICR genetic background to enhance breeding robustness and care of the young. These mice were backcrossed using a Jcl:ICR background for more than eight generations. We prepared mouse models of CRF by 5/6Nx operation (Ope) under sodium pentobarbital (40 mg/kg, i.p.) or diethyl ether anesthesia. 5/6Nx was performed in two stages. In the first surgical procedure (at 6 weeks of age), two-thirds of the left kidney was removed by cutting off both poles. Seven days later, the right kidney was completely removed. After the operation, mice were housed for 8 weeks (until they were 16 weeks old) in order to achieve CRF. Sham-operated (Sham) mice were subjected to laparotomy on the same days as the procedure in the 5/6Nx mice. This method was also used for treating Clk/Clk mice. Retinol-free food (A minus) was purchased form KBT ORIENTAL CO., LTD. To investigate the influences of retinol-free feeding on kidney, mice were fed from the fourth week to the eighth week after an operation.

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Retinol Dehydrogenase 10 Reduction Mediated Retinol Metabolism Disorder Promotes Diabetic Cardiomyopathy

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