Omega-3 fatty acid and menaquinone-7 combination are helpful for aortic calcification prevention, reducing osteoclast area of bone and Fox0 expression of muscle in uremic rats.

BACKGROUND: Osteopenia, sarcopenia, and vascular calcification (VC) are prevalent in patients with chronic kidney disease and often coexist. In the absence of proven therapies, it is necessary to develop therapeutic or preventive nutrients supplementation for osteopenia, sarcopenia, and VC. The present study investigated the effect of omega-3 fatty acid (FA) and menaquinone-7 (MK-7) on osteopenia, sarcopenia, and VC in adenine and low-protein diet-induced uremic rats. METHODS: Thirty-two male Sprague-Dawley rats were fed diets containing 0.75% adenine and 2.5% protein for three weeks. Rats were randomly divided into four groups that were fed diets containing 2.5% protein for four weeks: adenine control (0.9% saline), omega-3 FA (300 mg/kg/day), MK-7 (50 µg/kg/day), and omega-3 FA/MK-7. Von Kossa staining for aortic calcification assessment was performed. Osteoclast surface/bone surface ratio (OcS/BS) of bone and muscle fiber were analyzed using hematoxylin and eosin staining. Osteoprotegerin (OPG) immunohistochemical staining was done in the aorta and bone. Molecules related with sarcopenia were analyzed using western blotting. RESULTS: Compared to the normal control, OcS/BS and aortic calcification, and OPG staining in the aorta and bone were significantly increased in the adenine controls. OPG staining and aortic calcification progressed the least in the group supplemented with both omega-3 FA/MK-7. In the adenine controls, the regular arrangement of muscle fiber was severely disrupted, and inflammatory cell infiltration was more prominent. These findings were reduced after combined supplementation with omega-3 FA/MK-7. Furthermore, decreased mammalian target of rapamycin and increased Forkhead box protein 1 expression was significantly restored by combined supplementation. CONCLUSIONS: Combined nutrients supplementation with omega-3 FA and MK-7 may be helpful for aortic VC prevention, reducing osteoclast activation and improving sarcopenia-related molecules in adenine and low-protein diet induced uremic rats.

Effect of pravastatin on erythrocyte membrane fatty acid contents in patients with chronic kidney disease.

BACKGROUND: Statin treatment has decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid level is higher in patients with acute coronary syndrome. This study aimed to evaluate the effect of pravastatin on the erythrocyte membrane fatty acid (FA) contents in patients with CKD. METHODS: Sixty-two patients were enrolled from January 2017 to March 2019 (NCT02992548). Pravastatin was initially administered at a dose of 20 mg for 24 weeks. The pravastatin dose was increased to 40 mg after 12 weeks if it was necessary to control dyslipidemia. The primary outcome was change in erythrocyte membrane FA, including oleic acid, after pravastatin treatment for 24 weeks. RESULTS: Forty-five patients finished this study, and there was no adverse effect related to pravastatin. Compared with baseline, total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased after pravastatin treatment. Compared with baseline, saturated FA, oleic acid, and arachidonic acid levels were significantly increased and polyunsaturated FA and linoleic acid (LA) levels were significantly decreased after pravastatin treatment. There was also a decrease in eicosapentaenoic acid after pravastatin treatment in CKD patients with estimated glomerular filtration rate <60 mL/min/1.73 m2. CONCLUSION: Administration of pravastatin in patients with CKD leads to a decrease in FA known to be protective against the risk of CVD. Omega-3 FA or LA supplementation might be necessary to recover changes in erythrocyte membrane FA contents when pravastatin is used for treating dyslipidemia in patients with CKD.

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

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-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.

Combined Treatment with Omega-3 Fatty Acid and Cholecalciferol Increases 1,25-Dihydroxyvitamin D Levels by Modulating Dysregulation of Vitamin D Metabolism in 5/6 Nephrectomy Rats.

The protein 1α-hydroxylase (CYP27B1) was expressed in liver and omega-3 fatty acid (FA) elevated 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in dialysis patients. The aim of this study was to determine whether omega-3 FA and cholecalciferol have effects on vitamin D metabolism related to CYP27B1 and 24-hydroxylase (CYP24) activities in the kidney and liver of 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were divided into the following groups: sham control, 5/6 Nx, 5/6 Nx treated with cholecalciferol, 5/6 Nx treated with omega-3 FA, and 5/6 Nx treated with cholecalciferol/omega-3 FA. CYP27B1 and CYP24 expression were measured in the liver and kidney. Further, 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] levels were measured in serum. Among Nx groups, 1,25(OH)2D and 25(OH)D levels were lowest in the 5/6 Nx group. CYP24 expression was increased in the kidney of the 5/6 Nx rat model, which was found to be reversed by omega-3 FA or cholecalciferol/omega-3 FA supplementation. Decreased CYP27B1 expression was observed in the liver of the 5/6 Nx rats and its expression was recovered by supplementation with cholecalciferol/omega-3 FA. In conclusion, omega-3 FA and cholecalciferol may synergistically increase 1,25(OH)2D levels by inhibiting CYP24 expression in the kidney and liver and activating CYP27B1 expression in the liver of 5/6 Nx rats.

Supplementary nutrients for prevention of vascular calcification in patients with chronic kidney disease.

Vascular calcification (VC) and malnutrition associated with cardiovascular disease are common in patients with chronic kidney disease (CKD) treated with dialysis. VC, which reflects vascular aging, and malnutrition are also encountered in the non-CKD elderly population. This similarity of clinical findings suggests that the progression of CKD is related to aging and the existence of a causal relationship between VC and malnutrition. To retard renal progression, a low- or very-low-protein diet is usually recommended for CKD patients. Dietary education may induce malnutrition and deficiency of important nutrients, such as vitamins K and D. Menaquinone-7, a type of vitamin K2, is under investigation for inhibiting VC in elderly patients without CKD, as well as for prevention of VC in patients with CKD. Nutritional vitamin D, such as cholecalciferol, may be considered to decrease the required dose of active vitamin D, which increases the risk of VC due to increased calcium and phosphate loads. Omega-3 fatty acids are important nutrients and their ability to inhibit VC needs to be evaluated in clinical trials. This review focuses on the ability of supplementary nutrients to prevent VC in patients with CKD, in whom dietary restriction is essential.

Omega-3 fatty acid decreases oleic acid by decreasing SCD-1 expression in the liver and kidney of a cyclosporine-induced nephropathy rat model.

AIM: Stearoyl-CoA desaturase (SCD)-1 and elongase-6 (Elovl-6) are associated with fatty acid (FA) synthesis. We evaluated the effect of omega-3 FA on erythrocyte membrane FA contents through SCD-1 and Elovl-6 expression in the liver and kidney of a cyclosporine (CsA)-induced rat model. METHODS: Male Sprague Dawley rats were divided into control, CsA, and CsA treated with omega-3 FA groups. We measured SCD-1 and Elovl-6 expression levels via western blot and immunohistochemistry analysis. RESULTS: Erythrocyte membrane oleic acid content was lower in the CsA with omega-3 FA group compared to the CsA group. Compared to the control group, CsA-induced rats showed elevated SCD-1 expression in the kidney and liver, which omega-3 FA treatment reversed. Elovl-6 expression was increased in the liver, but decreased in the kidney in CsA group compared to control, which omega-3 FA treatment also reversed. CONCLUSIONS: Omega-3 FA supplementation decreased erythrocyte membrane oleic acid content by modulating SCD-1 and Elovl-6 expression in the kidney and liver of CsA-induced rats.

Impact of Blood or Erythrocyte Membrane Fatty Acids for Disease Risk Prediction: Focusing on Cardiovascular Disease and Chronic Kidney Disease.

Fatty acids (FAs) are essential nutrients and main constituents of cell membranes that are involved in the signaling pathway and associated with health conditions. We investigated if blood or erythrocyte membrane FAs can predict the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and related complications. Omega-3 (n-3) FAs are important predictors for metabolic syndrome, diabetes, CVD, and CKD risks, and the n-3 index is also a good biomarker for sudden cardiac death in coronary artery disease. Linoleic acid, which is one of the major n-6 FAs reflecting recent dietary FA intake, may predict CVD risk and mortality in the general population and patients with CKD. Monounsaturated FAs (MUFAs) are also related to diabetes or diabetic nephropathy. Oleic acid, a major MUFA, is an emerging marker that is related to acute coronary syndrome, low glomerular filtration rate, and vascular calcification in patients with CKD, and can be modified by n-3 FA supplementation. Saturated FAs, trans-FAs, and FA desaturation/elongation are associated with CVD risk; however, few studies have been conducted on patients with CKD. In summary, blood or erythrocyte membrane FA measurements are important for CVD and CKD risk prediction and management. Further studies are needed to elucidate the FAs for their risk predictions.

Effect of Omega-3 Fatty Acid on STAMP2 Expression in the Heart and Kidney of 5/6 Nephrectomy Rat Model.

Six transmembrane protein of prostate 2 (STAMP2) is a critical modulator of inflammation and metabolism in adipose tissue. There are no data on the expression of STAMP2 in chronic kidney disease, which is an inflammatory disease related to metabolic disorders. This study aimed to investigate STAMP2 expression in the kidney and heart in 5/6 nephrectomy (Nx) rats, and the effect of omega-3 fatty acid (FA) on STAMP2 expression. Male Sprague Dawley rats were divided into three groups: sham control (0.9% saline), 5/6 Nx (0.9% saline), and 5/6 Nx treated with omega-3 FA (300 mg per kg per day by gastric gavage). The expression of STAMP2 in the kidney and heart were examined by western blotting. Serum creatinine levels were higher in 5/6 Nx rats than in controls. Compared with sham controls, the expression of IκB, NF-κB, NOX4, SREBP-1, and LXR were upregulated and STAMP2 and phosphorylated-AMPK expression were downregulated in the kidney and heart of 5/6 Nx rats. Omega-3 FA supplementation prevented these changes in biomarkers related to inflammation and metabolic lipid disorders. Omega 3-FA supplementation induced the upregulation of STAMP2 protein in 5/6 Nx rats, which was associated with an attenuation of inflammation- and metabolic disease-related markers.

Effect of Omega-3 Fatty Acid on the Fatty Acid Content of the Erythrocyte Membrane and Proteinuria in Patients with Diabetic Nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease and is associated with an increased risk of cardiovascular events. Dietary omega-3 fatty acid (FA) has cardioprotective effect and is associated with a slower deterioration of albumin excretion in patients with diabetic nephropathy. In this study, we evaluated the effect of omega-3 FA on proteinuria in diabetic nephropathy patients who are controlling blood pressure (BP) with angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB). In addition, we identified changes in erythrocyte membrane FA contents. A total of 19 patients who were treated with ACEi or ARB for at least 6 months were treated for 12 weeks with omega-3 FA (Omacor, 3 g/day) or a control treatment (olive oil, 3 g/day). Proteinuria levels were unchanged after 12 weeks compared with baseline values in both groups. The erythrocyte membrane contents of omega-3 FA and eicosapentaenoic acid (EPA) were significantly increased, and oleic acid, arachidonic acid : EPA ratio, and omega-6 : omega-3 FA ratio were significantly decreased after 12 weeks compared with the baseline values in the omega-3 FA group. Although omega-3 FA did not appear to alter proteinuria, erythrocyte membrane FA contents, including oleic acid, were altered by omega-3 FA supplementation.

The effects of omega-3 fatty acid on vitamin D activation in hemodialysis patients: a pilot study.

The high incidence of cardiovascular disease and vitamin D deficiency in chronic kidney disease patients is well known. Vitamin D activation by omega-3 fatty acid (FA) supplementation may explain the cardioprotective effects exerted by omega-3 FA. We hypothesized that omega-3 FA and 25-hydroxyvitamin D (25(OH)D) supplementation may increase 1,25-dihydroxyvitamin D (1,25(OH)2D) levels compared to 25(OH)D supplementation alone in hemodialysis (HD) patients that have insufficient or deficient 25(OH)D levels. We enrolled patients that were treated for at least six months with 25(OH)D < 30 ng/mL (NCT01596842). Patients were randomized to treatment for 12 weeks with cholecalciferol supplemented with omega-3 FA or a placebo. Levels of 25(OH)D and 1,25(OH)2D were measured after 12 weeks. The erythrocyte membrane FA contents were also measured. Levels of 25(OH)D were increased in both groups at 12 weeks compared to baseline. The 1,25(OH)2D levels at 12 weeks compared to baseline showed a tendency to increase in the omega-3 FA group. The oleic acid and monounsaturated FA content decreased, while the omega-3 index increased in the omega-3 FA group. Omega-3 FA supplementation may be partly associated with vitamin D activation, although increased 25(OH)D levels caused by short-term cholecalciferol supplementation were not associated with vitamin D activation in HD patients.

Erythrocyte n-3 polyunsaturated fatty acids and the risk of type 2 diabetes in Koreans: a case-control study.

BACKGROUND: There is inconsistent epidemiologic evidence for an association between tissue levels of n-3 polyunsaturated fatty acids (PUFAs) and the risk of type 2 diabetes. The purpose of the present study was to investigate whether erythrocyte levels of n-3 PUFAs are negatively associated with the risk of type 2 diabetes and correlated with levels of glucose and HbA1c in Koreans. METHODS: A total of 130 patients with type 2 diabetes and 260 age- and sex-matched controls participated in this study. RESULTS: The risk of type 2 diabetes was negatively associated with erythrocyte levels of 22:5n3 and 22:6n3, which were negatively correlated with HbA1c levels after adjusting for age, sex and body mass index. Additionally, the risk of type 2 diabetes was negatively associated with erythrocyte levels of 18:0 and 20:4n6, but positively associated with erythrocyte levels of 16:0, 18:1n9, 18:3n3, 18:2n6, 18:3n6, n-6/n-3 PUFA ratio, 18:1t and 18:2n6t, and Δ-6 desaturase (18:3n6/18:2n6) and Δ-9 desaturase (18:1n9/18:0) activities. CONCLUSIONS: The risk of type 2 diabetes was negatively associated with erythrocyte levels of n-3 PUFA, which were negatively correlated with HbA1c levels in Koreans, suggesting that n-3 PUFAs might reduce the risk of type 2 diabetes in Asians.

Cardioprotective effects of ω -3 PUFAs in chronic kidney disease.

The prevalence rate of chronic kidney disease (CKD) is increasing worldwide, and cardiovascular disease (CVD) is a main cause of death in patients with CKD. The high incidence of CVD in CKD patients is related to chronic inflammation, dyslipidemia, malnutrition, atherosclerosis, and vascular calcification. Omega-3 polyunsaturated fatty acids ( ω -3 PUFAs) have been shown to reduce the risk of CVD. In this paper, we review the beneficial effects of ω -3 PUFAs on CVD and the possible cardioprotective mechanisms of ω -3 PUFAs in CKD patients by determining the effect of ω -3 PUFAs in the general population. ω -3 PUFAs have several cardioprotective benefits, such as reducing inflammation, decreasing oxidative stress, inhibiting platelet activity, exerting antiarrhythmic effects, and improving triglyceride levels, in the general population and patients with CKD. Modifications of erythrocyte membrane fatty acid content, including an increased ω -3 index and decreased oleic acid, after ω -3 PUFAs supplementation are important changes related to CVD risk reduction in the general population and patients with CKD. Further basic and clinical studies are essential to confirm the effects of ω -3 PUFAs on vitamin D activation, vascular calcification prevention, cardiovascular events, and mortality in CKD patients.

Rosuvastatin attenuates inflammation, apoptosis and fibrosis in a rat model of cyclosporine-induced nephropathy.

BACKGROUND/AIM: Cyclosporine (CsA)-induced kidney injury is characterized by renal dysfunction with inflammatory cell infiltrations, apoptosis and fibrosis. Pleiotropic effects of statins may exert anti-inflammatory, antiapoptotic and antifibrotic actions beyond lipid control. The aim of this study is to investigate whether rosuvastatin (RUS) has anti-inflammatory, antiapoptotic and antifibrotic effects on chronic CsA-induced nephropathy in a rat model. METHODS: Male Sprague-Dawley rats fed a low-sodium diet were divided into three treatment groups: control (0.9% saline injection), CsA (15 mg/kg/day by subcutaneous injection), CsA + RUS (10 mg/kg/day by gastric gavage). Renal function, CsA level and lipid levels were measured at the end of 4 weeks. The expression of ED-1, transforming growth factor-ß(1) (TGF-ß(1)) and α-smooth muscle actin (α-SMA) for inflammation and fibrosis were examined by Western blot analysis. The expression levels of apoptosis-associated factors were examined by Western blot analysis. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling (TUNEL) method. RESULTS: Kidney function was decreased in CsA-treated rats compared with controls, which was attenuated by RUS. RUS did not affect the lipid level or the blood CsA level. TUNEL staining showed that RUS inhibited CsA-induced tubular apoptosis. RUS decreased CsA-induced increased expression of Bax/Bcl-2 ratio. The expressions of ED-1, α-SMA, TGF-ß(1), Smad2/3, Smad4 and p-JNK were increased in CsA-treated rats, which were attenuated by RUS. Tubular atrophy and interstitial fibrosis in CsA-treated rats were attenuated by RUS supplementation. CONCLUSION: RUS supplementation attenuates proinflammatory and apoptosis-related factors and inhibits the fibrotic pathways including the smad-dependent and smad-independent pathways in a rat model of CsA-induced nephropathy.

Effects of low-dose niacin on dyslipidemia and serum phosphorus in patients with chronic kidney disease.

BACKGROUND: Niacin supplementation improves dyslipidemia and lowers serum phosphorus levels in patients with chronic kidney disease (CKD). We evaluated whether low-dose niacin supplementation can improve dyslipidemia, lower serum phosphorus levels, and be administered with a low frequency of adverse effects in patients with CKD. METHODS: We retrospectively analyzed the clinical records of patients with CKD who had taken niacin from January 2009 to June 2011. We excluded patients with CKD stage 1 and 5. We then enrolled 31 patients with CKD who had taken niacin at a fixed dose of 500 mg/day for 6 months. We also randomly selected 30 patients with CKD who had been taking statin for 9 months as a control group. RESULTS: Among the 34 patients with CKD who were prescribed niacin, five (14%) complained of adverse effects, and three (8%) discontinued niacin. The proportion of patients in the niacin group who had been taking a statin or omega-3 fatty acids was 67.7% and 48.8%, respectively. In the niacin group, high-density lipoprotein cholesterol level was significantly increased and triglyceride level was significantly decreased at 12 and 24 weeks compared with baseline levels (P<0.05). In the niacin group, phosphorous level (P<0.05) was significantly decreased, and glomerular filtration rate (GFR) was significantly increased (P<0.05) at 24 weeks compared with baseline values. CONCLUSION: Low-dose niacin had a low frequency of adverse effects and also improved dyslipidemia, lowered serum phosphorus level, and increased GFR in patients with CKD. Further studies are needed to evaluate the long-term effects of low-dose niacin for renal progression of CKD.

Omega-3 fatty acid supplementation increases 1,25-dihydroxyvitamin D and fetuin-A levels in dialysis patients.

Vitamin D deficiency, low levels of fetuin-A, and fibroblast growth factor 23 (FGF-23) are related to vascular calcification, which is associated with cardiovascular disease. We hypothesized that omega-3 fatty acid (FA), which has cardioprotective properties, modifies vitamin D status, fetuin-A, and FGF-23 levels in dialysis patients. In a randomized, open-label, controlled study, a total of 47 patients treated with dialysis for at least 1 year were randomized to treatment for 6 months with omega-3 FAs (Omacor, 3 g/d; Pronova, Sandefjord, Norway) or a control group. Levels of fetuin-A and FGF-23 were measured by enzyme-linked immunoassay, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured by radioimmunoassay. The mean age of the enrolled patients was 57.4 ± 10.4 years, and mean dialysis duration was 46.5 ± 28.1 months. Twenty-seven hemodialysis patients and 16 peritoneal dialysis patients finished this trial. After 6 months, the levels of 1,25-dihydroxyvitamin D and fetuin-A were significantly increased in the group taking the omega-3 FA supplement compared with baseline. Levels of calcium, phosphorous, parathyroid hormone, 25-hydroxyvitamin D, FGF-23, and lipid profiles were not significantly changed in the omega-3 FA-supplemented group after 6 months compared with baseline. The erythrocyte membrane contents of eicosapentaenoic acid and docosahexaenoic acid were significantly increased, and oleic acid content was significantly decreased in the omega-3 FA-supplemented group after 6 months compared with baseline. Regarding vascular calcification and cardiovascular disease, omega-3 FA supplementation may have a clinical benefit caused by activating vitamin D, increasing fetuin-A levels, and modifying erythrocyte membrane FA contents in dialysis patients.

Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney.

Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.