TY - JOUR

T1 - Fish oil replacement prevents, while docosahexaenoic acid-derived protectin DX mitigates end-stage-renal-disease in atherosclerotic diabetic mice

AU - Perazza, Lais R.

AU - Mitchell, Patricia L.

AU - Lizotte, Farah

AU - Jensen, Benjamin A. H.

AU - St-Pierre, Philippe

AU - Trottier, Jocelyn

AU - Barbier, Olivier

AU - Mathieu, Patrick

AU - Geraldes, Pedro M.

AU - Marette, Andre

PY - 2021

Y1 - 2021

N2 - Diabetic nephropathy (DN) remains the major cause of end-stage renal disease (ESRD). We used high-fat/high-sucrose (HFHS)-fed LDLr-/- /ApoB(100/100) mice with transgenic overexpression of IGFII in pancreatic beta-cells (LRKOB100/IGFII) as a model of ESRD to test whether dietary long chain omega-3 polyunsaturated fatty acids LC omega 3FA-rich fish oil (FO) could prevent ESRD development. We further evaluated the potential of docosahexaenoic acid (DHA)-derived pro-resolving lipid mediators, 17-hydroxy-DHA (17-HDHA) and Protectin DX (PDX), to reverse established ESRD damage. HFHS-fed vehicle-treated LRKOB100/IGFII mice developed severe kidney dysfunction leading to ESRD, as revealed by advanced glomerular fibrosis and mesangial expansion along with reduced percent survival. The kidney failure outcome was associated with cardiac dysfunction, revealed by reduced heart rate and prolonged diastolic and systolic time. Dietary FO prevented kidney damage, lean mass loss, cardiac dysfunction, and death. 17-HDHA reduced podocyte foot process effacement while PDX treatment alleviated kidney fibrosis and mesangial expansion as compared to vehicle treatment. Only PDX therapy was effective at preserving the heart function and survival rate. These results show that dietary LC omega 3FA intake can prevent ESRD and cardiac dysfunction in LRKOB100/IGFII diabetic mice. Our data further reveals that PDX can protect against renal failure and cardiac dysfunction, offering a potential new therapeutic strategy against ESRD.

AB - Diabetic nephropathy (DN) remains the major cause of end-stage renal disease (ESRD). We used high-fat/high-sucrose (HFHS)-fed LDLr-/- /ApoB(100/100) mice with transgenic overexpression of IGFII in pancreatic beta-cells (LRKOB100/IGFII) as a model of ESRD to test whether dietary long chain omega-3 polyunsaturated fatty acids LC omega 3FA-rich fish oil (FO) could prevent ESRD development. We further evaluated the potential of docosahexaenoic acid (DHA)-derived pro-resolving lipid mediators, 17-hydroxy-DHA (17-HDHA) and Protectin DX (PDX), to reverse established ESRD damage. HFHS-fed vehicle-treated LRKOB100/IGFII mice developed severe kidney dysfunction leading to ESRD, as revealed by advanced glomerular fibrosis and mesangial expansion along with reduced percent survival. The kidney failure outcome was associated with cardiac dysfunction, revealed by reduced heart rate and prolonged diastolic and systolic time. Dietary FO prevented kidney damage, lean mass loss, cardiac dysfunction, and death. 17-HDHA reduced podocyte foot process effacement while PDX treatment alleviated kidney fibrosis and mesangial expansion as compared to vehicle treatment. Only PDX therapy was effective at preserving the heart function and survival rate. These results show that dietary LC omega 3FA intake can prevent ESRD and cardiac dysfunction in LRKOB100/IGFII diabetic mice. Our data further reveals that PDX can protect against renal failure and cardiac dysfunction, offering a potential new therapeutic strategy against ESRD.

KW - CVD

KW - diabetic nephropathy

KW - end-stage renal disease

KW - omega-3 fatty acids

KW - protectin DX

KW - GROWTH-FACTOR-II

KW - LEFT-VENTRICULAR HYPERTROPHY

KW - POLYUNSATURATED FATTY-ACIDS

KW - CARDIOVASCULAR-DISEASE

KW - EXTRACELLULAR-MATRIX

KW - INSULIN-RESISTANCE

KW - LIPID MEDIATORS

KW - TRANSGENIC MICE

KW - KIDNEY-DISEASE

KW - BLOOD-PRESSURE

U2 - 10.1096/fj.202100073R

DO - 10.1096/fj.202100073R

M3 - Journal article

C2 - 33835594

VL - 35

JO - F A S E B Journal

JF - F A S E B Journal

SN - 0892-6638

IS - 5

M1 - 21559

ER -