1). REPC express ecto-5′-nucleotidase (CD73) and platelet-derived growth factor receptor β-polypeptide (PDGFRB),[9] and [13] both are also markers of pericytes and EPO-negative interstitial fibroblasts.14Epo expression in tubular epithelial cells appears to be suppressed by GATA transcription factors, in particular GATA-2 and GATA-3, and can be reactivated under normoxic

or hypoxic conditions when the GATA core consensus binding sequence upstream of the Epo transcription start site is mutated. 11 The kidney responds to hypoxia by increasing the number of REPC in an O2-dependent manner and therefore regulates EPO output through adjustments in REPC number. [8] and [11] O2-dependent Epo transcription is controlled by distinct regulatory DNA sequences. These Metformin flank the Epo coding sequence on both sides, the kidney-inducibility element Carfilzomib research buy in the 5′-region and the liver-inducibility element in the 3′-region. [15], [16] and [17] The 3′-hypoxia enhancer region is absolutely required for the hypoxic induction of Epo in the liver, as shown by genetic studies in mice. 18 REPC have been visualized

in BAC transgenic mice through the use of green fluorescent protein (GFP). In this transgenic model the Epo coding sequence was replaced by GFP cDNA, which brings GFP under the control of Epo regulatory elements. 11 GFP expression was found in renal peritubular interstitial cells and in a subpopulation of hepatocytes that were localized around the central vein, supporting the notion that these two cell types represent the major sites of physiologic EPO production under conditions of systemic hypoxia. In the kidney, GFP-positive interstitial cells were unique in their morphologic appearance,

as they displayed dendrite-like processes and expressed neuronal-specific markers, such as microtubule-associated protein 2 (MAP2) and neurofilament protein light polypeptide (NFL), indicating that REPC may be derived from progenitor cells of neuronal origin. This notion is furthermore supported by lineage tracing studies that utilized myelin protein zero (P0)-Cre transgenic mice, which express Cre-recombinase in neural crest-derived cells. 13 In keeping with this observation, Frede and colleagues 3-mercaptopyruvate sulfurtransferase established an EPO-producing renal tumor cell line with similar morphologic and molecular characteristics. 19 Although the hypoxic induction of Epo was reported in 4E cells, a mesenchymal cell clone with characteristics of embryonic kidney stromal cells, 20 primary REPC that retain their EPO-producing ability are difficult to culture. The molecular mechanisms underlying this phenomenon are unclear. Transdifferentiation of REPC into myofibroblasts, which are a main source of collagen in fibrotic kidneys, has been proposed as a potential mechanism by which REPC loose their ability to synthesize EPO in CKD ( Fig. 1).