Abstract
Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.
Highlights
Diabetic nephropathy (DN) is a major microvascular complication in patients with diabetes mellitus, leading to endstage renal diseases [1]
The expression of Nuclear hormone receptors (NHRs) in mouse kidney tissue (C57/BL6 and db/m) and renal cell lines was determined by quantitative RT-PCR (qPCR) analysis
We analyzed NHR expression in db/m mice and renal cell lines (Figs. 2B–F, 3, 4, and 5). This format is consistent with previous NHR expression analyses and provides a basis for comparison with cell lines commonly associated with each receptor type. Because this survey focused on expression in a select few cell types, we could analyze RNA levels for all receptors in a single assay for direct comparison of NHR levels within a given tissue
Summary
Diabetic nephropathy (DN) is a major microvascular complication in patients with diabetes mellitus, leading to endstage renal diseases [1]. The incidence of DN is increasing rapidly with the increase in patients with type 2 diabetes and metabolic syndrome, and at present accounts for almost 50% of all end-stage renal diseases [2] It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. Various pathogenic mechanisms of DN have been proposed including increased expression of advanced glycation end-products, protein kinase C, transforming growth factor b, and reactive oxygen species. In addition to these metabolic derangements, changes in the glomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, synergistically exacerbate the progression of DN. Identification of additional causative factors leading to renal injury and the development of novel agents to prevent or treat DN are urgently needed
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