Dimethyl fumarate is an FDA-approved oral immunomodulatory drug with anti-inflammatory properties that induces the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2. The aim of this study was to determine the efficacy of dimethyl fumarate on interstitial inflammation and renal cyst growth in a preclinical model of nephronophthisis. Four-week-old female Lewis polycystic kidney disease (a genetic ortholog of human nephronophthisis-9) rats received vehicle (V), 10 mg/kg (D10) or 30 mg/kg (D30) (n = 8–9 each) dimethyl fumarate in drinking water for eight weeks. Age-matched Lewis control rats were also studied (n = 4 each). Nuclear factor erythroid-derived factor 2 was quantified by whole-slide image analysis of kidney sections. Renal nuclear factor erythroid-derived factor 2 activation was partially reduced in vehicle-treated Lewis polycystic kidney disease rats compared to Lewis control (21.4 ± 1.7 vs. 27.0 ± 1.6%, mean ± SD; P < 0.01). Dimethyl fumarate upregulated nuclear factor erythroid-derived factor 2 in both Lewis Polycystic Kidney Disease (D10: 35.9 ± 3.8; D30: 33.6 ± 3.4%) and Lewis rats (D30: 34.4 ± 1.3%) compared to vehicle-treated rats (P < 0.05). Dimethyl fumarate significantly reduced CD68+ cell accumulation in Lewis polycystic kidney disease rats (V: 31.7 ± 2.4; D10: 23.0 ± 1.1; D30: 21.5 ± 1.9; P < 0.05). In Lewis polycystickidney disease rats, dimethyl fumarate did not alter the progression of kidney enlargement(V: 6.4 ± 1.6; D10: 6.9 ± 1.2; D30: 7.3 ± 1.3%) and the percentage cystic index (V:59.1 ± 2.7; D10: 55.7 ± 3.5; D30: 58.4 ± 2.9%). Renal dysfunction, as determined by theserum creatinine (Lewis + V: 26 ± 4 vs. LPK + V: 60 ± 25 P < 0.01;LPK + D10: 47 ± 7; LPK + D30: 47 ± 9 µmol/L), and proteinuria were also unaffected bydimethyl fumarate treatment. In conclusion, the upregulation of nuclear factorerythroid-derived factor 2 by dimethyl fumarate reduced renal macrophage infiltration innephronophthisis without adverse effects, suggesting that it could potentially be used incombination with other therapies that reduce the rate of renal cyst growth.Impact statementThis is the first study to investigate the effects of dimethyl fumarate in a model ofcystic kidney disease. The study assessed the therapeutic efficacy of dimethyl fumaratein upregulating renal nuclear factor erythroid-derived factor 2 expression, reducingmacrophage accumulation and cyst progression in a Lewis polycystic kidney disease ratmodel. This study demonstrates that dimethyl fumarate significantly upregulated renalnuclear factor erythroid-derived factor 2 expression and attenuates renal macrophageinfiltration, but had no effect on renal cyst progression, cardiac enlargement, andimproving renal function.
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