Abstract
Nuclear hormone receptors of the NR4A subgroup have been implicated in cancer, atherosclerosis, and most prominently in metabolic disease. However, little is known about the role of NR4A1 in kidney health or disease. Fawn-hooded hypertensive (FHH) Nr4a1 -/- deficient animals were evaluated for blood pressure, proteinuria, renal function and metabolic parameters from 4-24 weeks of age. At week 24, Nr4a1 -/- rats exhibited 4-fold higher proteinuria (81±11.5 mg/24hrs/100gBW) compared to FHH (21±1.0). No difference in telemetry measured blood pressure was observed at any time point, but glomerular filtration rate was significantly decreased in the Nr4a1 -/- (542±78.9 ul/min/gKW) vs FHH (937±75.2). Moderate increases in glomerulosclerosis were seen, but were not different between strains. The severity of tubular atrophy, casts, and fibrosis was significantly increased in Nr4a1 -/- compared to FHH (19±1.86% vs 12±0.8%, respectively). Tubulointerstitial macrophage infiltration was also significantly increased in kidneys from Nr4a1 -/- (245±62 foci per field) compared to FHH (50±13.4) at week 24. Microarray analysis of kidney from week 8-24 found significant up-regulation of important immune mediators, including TGF-β1-2, CCL2 (MCP-1), CCL9 (MIP-1γ), and other chemokines and interleukins. The specific injury (tubulointerstitial), immune cell infiltration, and immune gene expression profile led to the hypothesis that loss of Nr4a1 contributes to the observed injury by an immune-mediated mechanism. To test this hypothesis, bone marrow (bm) cross transplantation studies were performed in 3 groups of irradiated (irr) animals: (1) bmFHH into irrFHH (FHH control); (2) bmFHH into irrNr4a1 -/- ; and (3) bmNr4a1 -/- into irrNr4a1 -/- (Nr4a1 control). The bmFHH into irrNr4a1 -/- animals showed a significant attenuation of proteinuria starting as early as week 12 and continuing through week 24 (35±4.6 mg/24hrs/100gBW) compared to the Nr4a1 -/- control (60±7.5). These data strongly suggest that the mechanism of Nr4a1 -/- renal injury is mediated via an immune mechanism, likely due to the predisposition of the FHH to develop renal injury. Further studies are now underway to better understand the precise immune mechanism that promotes injury in this model.
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