Genetic Susceptibility and Loss of Nr4a1 Enhances Macrophage-Mediated Renal Injury in CKD

Abstract

Nuclear hormone receptors of the NR4A subgroup have been implicated in cancer, atherosclerosis, and metabolic disease. However, little is known about the role of these receptors in kidney health or disease. Nr4a1-deficient rats (Nr4a1 The incidence of CKD has increased over the last 2 decades. 1 Current estimates suggest that approximately 10% of adults in the United States have CKD. 2 Considering only federal Medicare spending, the direct economic effect of CKD is staggering. The cost to treat CKD (predialysis) in 2010 was $41 billion, in addition to ESRD (dialysis and transplantation) costs estimated at $32.9 billion. 3 A significant problem is that current treatment options are not ideal and only serve to slow the progression of CKD. Thus, the identification of genes and/or biologic pathways that mediate progressive kidney disease is critical to both developing new and/or improved treatments for CKD and curbing the associated financial burden. Nuclear hormone receptors are transcription factors that play a role in a variety of biologic processes and are induced in multiple tissues by diverse stimuli, such as b-adrenoceptor agonists, cold, fatty acids, glucose, insulin, and cholesterol. 4 The nuclear receptor (NR) 4A subgroup of nuclear hormone receptors is composed of three members: Nr4a1 (Nur77), Nr4a2 (Nurr1), and Nr4a3 (Nor1). In contrast with other NRs, the activity of NR4A receptor family is ligand independent and regulated at the level of gene expression and protein stability. 5 The NR4A subgroup has been linked to cancer, 6

Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model

“…57,58 At 10 months, MAP was measured by indwelling catheter, and animals were euthanized for collection of serum, organ weights, and histologic analysis. 57,58 Careful animal dissections were performed to investigate the nature and type of other urogenital abnormalities that occurred along with unilateral renal agenesis. Animals from three generations (n=487 animals) were analyzed to determine the frequency of unilateral renal agenesis in both female and male animals.…”

“…At month 5, MAP and RBF were measured as previously described. 57,58 Protocol 5: Temporal Study of Renal Injury in HSRA-S, HSRA-C, and Uninephrectomized HSRA-C Rats Four groups of male animals were established to study the time course development of proteinuria: (1) HSRA-S, (2) HSRA-C, (3) HSRA-UNX3 (uninephrectomized at 3 weeks of age), and (4) HSRA-UNX8 (uninephrectomized at 8 weeks of age). Uninephrectomy was performed using two-kidney (HSRA-C) animals, and sham operations were performed on littermate HSRA-S animals.…”

“…Rats were kept in metabolic cages for 24 hours with free access to water, and proteinuria was determined as previously described. 57,58 Upon euthanasia, kidney and heart samples were processed for histologic examination, and serum samples were obtained from cardiac puncture to measure blood parameters as done previously. 57,58 Protocol 6: BP and Renal Hemodynamic Parameters At 5, 15, and 20 months of age (n=6-13 rats per group/time), MAP, RBF, and FITC-inulin GFR were measured as previously described.…”

“…57,58 Upon euthanasia, kidney and heart samples were processed for histologic examination, and serum samples were obtained from cardiac puncture to measure blood parameters as done previously. 57,58 Protocol 6: BP and Renal Hemodynamic Parameters At 5, 15, and 20 months of age (n=6-13 rats per group/time), MAP, RBF, and FITC-inulin GFR were measured as previously described. 57,58 At the end of each experiment, the kidneys were removed and weighed, along with the heart.…”

“…57,58 Protocol 6: BP and Renal Hemodynamic Parameters At 5, 15, and 20 months of age (n=6-13 rats per group/time), MAP, RBF, and FITC-inulin GFR were measured as previously described. 57,58 At the end of each experiment, the kidneys were removed and weighed, along with the heart. Tissues were processed for histologic examination.…”