OLIVER OEY, PADMASHREE RAO, MAGDALENA LUCIUK, CARLY MANNIX, ANNETTE WONG, GOPALA RANGAN
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, 2145.
Aim: To determine the long-term efficacy of dimethyl fumarate (DMF) on interstitial inflammation and renal cyst growth in a preclinical model of polycystic kidney disease (PKD).
Background: Renal macrophage infiltration mediates the progression of kidney cyst growth in PKD. DMF is an FDA-approved oral immunomodulatory drug with anti-inflammatory properties that induce the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2 (Nrf-2).
Methods: Four-week-old female Lewis Polycystic Kidney Disease (LPK) rats received either vehicle (V),10mg/kg (D10) or 30mg/kg (D30) (n=8-9 each) DMF in drinking water for 8 weeks. Age-matched Lewis control rats were also studied (n=4 each). Nrf-2 was quantified by whole-slide image analysis of kidney sections.
Results: Renal Nrf-2 activation was partially reduced in vehicle-treated LPK rats compared to Lewis controls (21.4+1.7% vs. 27.0+1.6%, mean+SD; P<0.01). DMF upregulated Nrf2 in both LPK (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). DMF significantly reduced CD68+ cell accumulation in both Lewis (V: 23.8+2.6%; D30: 17.3+1.3%, P<0.05) and LPK rats (V: 31.7+2.4%; D10: 23.0+1.1%; D30: 21.5+1.9%; P<0.05). In LPK rats, DMF 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, determined by the serum creatinine (Lewis+V: 26+4 µmol/L vs. LPK+V: 60+25 µmol/L P<0.01; LPK+D10: 47+7 µmol/L; LPK+D30: 47+9 µmol/L), and proteinuria (data not shown) were also unaffected by DMF treatment.
Conclusions: The upregulation of Nrf2 by DMF reduced renal macrophage infiltration in PKD without adverse effects. These data suggest that DMF is a compound that could be potentially used in combination with other approaches that reduce renal cyst growth.