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Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1Α Via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model

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Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1Α Via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model marine drugs Article Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1α via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model Sung Hyun Son 1,† , Su Mi Lee 2,† , Mi Hwa Lee 3, Young Ki Son 2, Seong Eun Kim 2 and Won Suk An 2,* 1 Department of Internal Medicine, BHS Han Seo Hospital, Busan 48253, Korea; sohnseung@hanmail.net 2 Department of Internal Medicine, Dong-A University, Busan 49201, Korea; sumilee@dau.ac.kr (S.M.L.); kidney@dau.ac.kr (Y.K.S.); sekim@dau.ac.kr (S.E.K.) 3 Department of Anatomy and Cell Biology, Dong-A University, Busan 49201, Korea; hero15p@nate.com * Correspondence: anws@dau.ac.kr; Tel.: +82-51-240-2811 † These authors contributed equally to this work. Abstract: Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC- 1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP- activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC- Citation: Son, S.H.; Lee, S.M.; Lee, 1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined M.H.; Son, Y.K.; Kim, S.E.; An, W.S. through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, Omega-3 Fatty Acids Upregulate SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated SIRT1/3, Activate PGC-1α via PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein Deacetylation, and Induce Nrf1 expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar Production in 5/6 Nephrectomy Rat among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Model. Mar. Drugs 2021, 19, 182. Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and https://doi.org/10.3390/md19040182 deacetylation of PGC-1α, which was triggered by SIRT1/3. Academic Editor: Keywords: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; nuclear respira- Constantina Nasopoulou tory factor 1; nuclear factor erythroid 2-related factor 2; sirtuin 1; sirtuin 3; omega-3 fatty acid Received: 19 March 2021 Accepted: 23 March 2021 Published: 26 March 2021 1. Introduction Publisher’s Note: MDPI stays neutral Kidneys are involved in regulating several functions, including various metabolic with regard to jurisdictional claims in pathways, water and electrolyte balance, blood pressure control, and production of several published maps and institutional affil- hormones. As these functions consume enormous energy, kidneys are rich in mitochon- iations. dria [1]. Mitochondria can adapt to different metabolic conditions via regulating mecha- nistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)-mediated nutrient sensing pathways to maintain healthy mitochondrial population [2]. Among the studies on mitochondria, to date, there are only a few studies on mitochon- Copyright: © 2021 by the authors. drial biogenesis. Most studies related to mitochondrial biogenesis are based on non-renal Licensee MDPI, Basel, Switzerland. tissue [3,4], and studies on kidneys are mainly related to acute kidney injury (AKI) animal This article is an open access article models, proximal tubular cells, and diabetic nephropathy [5–7]. Although mitochondrial distributed under the terms and biogenesis may link to pathogenesis of mitochondrial dysfunction in non-diabetic chronic conditions of the Creative Commons kidney disease (CKD), research on this topic is also very limited. CKD and mitochondrial Attribution (CC BY) license (https:// biogenesis are related to cardiovascular disease [8,9]. Improving mitochondrial biogenesis creativecommons.org/licenses/by/ may be beneficial for cardioprotection in CKD. 4.0/). Mar. Drugs 2021, 19, 182. https://doi.org/10.3390/md19040182 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2021, 19, x FOR PEER REVIEW 2 of 10 Mar. Drugs 2021, 19, 182 mitochondrial biogenesis are related to cardiovascular disease [8,9]. Improving mitochon-2 of 10 drial biogenesis may be beneficial for cardioprotection in CKD. A study indicating that omega-3 fatty acids (FAs) facilitate the biogenesis of mito- chondriaA study was indicating conducted that using omega-3 non-kidney fatty acidstissues (FAs) [3,10]. facilitate A recent the study biogenesis demonstrated of mito- a chondriapromising was role conducted of omega-3 using FAs non-kidneyin mitochondria tissuesl biogenesis [3,10]. A in recent animal study models demonstrated with cardi- aovascular promising and role neurodegenerative of omega-3 FAs in diseases mitochondrial [11]. Therefore, biogenesis in the in animalpresent models study, we with aimed car- diovascularto investigate and mitochondrial neurodegenerative biogenesis diseases in kidneys [11]. Therefore,of 5/6 nephrectomy in the present (Nx) rats. study, Addi- we aimedtionally, to investigatewe evaluated mitochondrial the effect of biogenesisomega-3 FAs in kidneyson mitochondrial of 5/6 nephrectomy biogenesis (Nx)using rats. this Additionally,model. we evaluated the effect of omega-3 FAs on mitochondrial biogenesis using this model. 2. Results 2.2.1. Results Changes in Kidney Function and Histological Findings 2.1. Changes in Kidney Function and Histological Findings Compared to the control group, blood urea nitrogen (BUN) level in the Nx and Nx treatedCompared with omega-3 to the FA control groups group, were blood significan ureatly nitrogen increased (BUN) (control level group in the 17.7 Nx ± and 1.5, Nx Nx treatedgroup 77.7 with ± omega-3 28.4, and FA Nx groups with omega-3 were significantly FA group increased63.9 ± 17.0 (control mg/dL, group p = 0.007). 17.7 ±Although1.5, Nx groupthere 77.7was ±no28.4, significant and Nx withdifference omega-3 between FA group the 63.9 Nx ±and17.0 Nx mg/dL, treatedp = with 0.007). omega-3 Although FA theregroups, was BUN no significant levels were difference numerically between lower the Nxin the and Nx Nx treated treated with omega-3omega-3 FAFA groups, group. BUNThe serum levels werecreatinine numerically (sCr) level lower among in the the Nx thr treatedee groups with was omega-3 similar FA to group. that of TheBUN serum (con- creatininetrol group, (sCr) 0.4 ± level0.0; Nx among group, the 1.3 three ± 0.6; groups omega-3 was FA, similar 1.0 ± 0.3 to thatmg/dL; of BUN p = 0.008). (control Compared group, 0.4 ± 0.0; Nx group, 1.3 ± 0.6; omega-3 FA, 1.0 ± 0.3 mg/dL; p = 0.008). Compared to the to the control group, severe tubular dilatation and atrophy were observed using PAS control group, severe tubular dilatation and atrophy were observed using PAS staining staining in the Nx group (Supplementary Figure S1). Furthermore, the results showed that in the Nx group (Supplementary Figure S1). Furthermore, the results showed that the Nx the Nx treated with omega-3 FA group exhibited less tubulointerstitial changes than the treated with omega-3 FA group exhibited less tubulointerstitial changes than the Nx group. Nx group. The renal function and histological changes in the three groups have already The renal function and histological changes in the three groups have already been reported been reported in a previous study [12]. in a previous study [12]. 2.2.2.2. ChangesChanges inin FactorsFactors RelatedRelated toto MitochondrialMitochondrial BiogenesisBiogenesis 2.2.1.2.2.1. Nrf1Nrf1 andand Nrf2Nrf2 ExpressionExpression ComparedCompared toto the the control control group, group, the the Nx Nx group group showed showed significantly significantly decreased decreased expres- ex- sionpression level level of nuclear of nuclear respiratory respiratory factor factor 1 (Nrf1) 1 (Nrf1) and nuclear and nuclear factor erythroidfactor erythroid 2-related 2-related factor 2factor (Nrf2). 2 (Nrf2). However, However, in the Nx in treatedthe Nx treated with omega-3 with omega-3 FA group, FA the group, expression the expression level of Nrf1level andof Nrf1 Nrf2 and was Nrf2 significantly was significantly increased increased compared compared to the Nx to group, the Nx but group, did not but reach did not the levelreach ofthe control level of group control (Figure group1, Supplementary(Figure 1, Supplemen Figuretary S2). Figure These S2). results These were results also foundwere also in Nrf1found mRNA in Nrf1 quantitative mRNA quantitative real-time PCRreal-time analysis PCR (Supplementary analysis (Supplementary Figure S3). Figure S3). Figure 1. Expressions of (A) Nrf1 and (B) Nrf2 (n = 6/group). Decreased Nrf 1 and Nrf2 expressions Figure 1. Expressions of (A) Nrf1 and (B) Nrf2 (n = 6/group). Decreased Nrf 1 and Nrf2 expres- of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 (mean sions of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 a values(meanare values significantly are significantly different different from control). from control).p value <a p 0.05 value (mean < 0.05 values (mean are values significantly are signifi- different fromcantly the different Nx group). from the Nx group). 2.2.2. Changes in PGC-1α Expression and Its Activity The expression of peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC-1α) in the Nx group was significantly decreased compared to the control group. The Nx treated with omega-3 FA group showed significantly increased PGC-1α Mar. Drugs 2021, 19, x FOR PEER REVIEW 3 of 10 2.2.2.
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