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Biochimica et Biophysica Acta
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a d i s
Nuclear receptors in renal disease☆
Moshe Levi ⁎
Department of Medicine, Division of Nephrology and Hypertension, University of Colorado Denver, CO, USA
a r t ic l e
i n f o
a b s t r a c t
Diabetes is the leading cause of end-stage renal disease in developed countries. In spite of excellent glucose and blood pressure control, including administration of angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy still develops and progresses. The development of additional protective therapeuticinterventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, and inﬂammation. These receptors also modulate the development of ﬁbrosis. As a result of their diverse biological effects, nuclear hormone receptors have become major pharmaceutical targets for the treatment of metabolic diseases. The increasing prevalence ofdiabetic nephropathy has led intense investigation into the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. This role of nuclear hormone receptors would be associated with improvements in metabolism, the immune response, and inﬂammation. Several nuclear receptor activating ligands (agonists) have been shown to have a renal protective effect inthe context of diabetic nephropathy. This review will discuss the evidence regarding the beneﬁcial effects of the activation of several nuclear, especially the vitamin D receptor (VDR), farnesoid X receptor (FXR), and peroxisome-proliferator-associated receptors (PPARs) in preventing the progression of diabetic nephropathy and describe how the discovery and development of compounds that modulatethe activity of nuclear hormone receptors may provide potential additional therapeutic approaches in the management of diabetic nephropathy. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. Published by Elsevier B.V.
Article history: Received 13 January 2011 Received in revised form 21 March 2011 Accepted 6 April 2011 Available online 14April 2011 Keywords: Diabetes Nuclear hormone receptors Renal disease VDR FXR PPAR
1. Introduction Diabetes mellitus is the most common cause of end-stage renal disease in the developed world requiring dialysis or renal transplantation for the maintenance of life. The pathogenesis of diabetic nephropathy is multifactorial. Hypertension, abnormal carbohydrate metabolism, abnormal lipid metabolism,accumulation of lipids, upregulation of proﬁbrotic growth factors (including, renin, angiotensin II, transforming growth factor β [TGF-β] and vascular endothelial growth factor [VEGF]), upregulation of proinﬂammatory cytokines (including, nuclear factor kappa B [NF-κB], CCL2, also known as MCP1, tumor necrosis factor [TNF] and interleukin 1β [IL-1β]), increased oxidative stress, and increasedproduction of advanced glycation end products all have an important role in the pathogenesis and progression of diabetic nephropathy [1–4]. In spite of all the beneﬁcial interventions implemented in patients with diabetes, including tight glucose control, tight blood pressure
☆ This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. ⁎ 12700 East 19thAvenue, Research 2, Room 7002, Box C281, Aurora, CO 80045, USA. Tel.: +1 303 724 4825; fax: +1 303 724 4868. E-mail address: email@example.com. 0925-4439/$ – see front matter Published by Elsevier B.V. doi:10.1016/j.bbadis.2011.04.003
control, and angiotensin II receptor antagonism, renal injury progresses in most of these patients. Additional treatment modalities that modulate the...