Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Abstract

CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFkB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFkB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFkB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.

Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis

“…Although the reversibility of fibrosis has been shown by the administration of tamoxifen, 13 dexamethasone, 13,28 and other renoprotective reagents, this is the first report showing the spontaneous reversal of fibrosis secondary to tubular injury without additional treatment. On the other hand, we showed that repeated mild proximal tubule injuries can cause sustained interstitial fibrosis.…”

“…Ccl2 and IL-6 mRNA expression was also increased when cocultured with NRK52E cells pretreated with TGFb1 ( Figure 6C), indicating the acquisition of an inflammatory phenotype. 27,28 These results indicate that damaged tubules might secrete factors that either directly or indirectly (via enhanced inflammatory cell recruitment) promote fibroblast transition.…”

Physiology of the Renal Interstitium

“…Two recent studies that used transgenic mice harboring a 180-kD chromosome fragment erythropoietin transgene reported that de novo expression of a-smooth muscle antibody in interstitial fibroblasts correlates negatively with Epo expression, suggesting that additional superimposed intracellular programs render the Epo gene unresponsive to transcriptional stimuli (48,49). In this regard, differential expression of hypoxia-inducible factor (HIF) proteins, of globin transcription factor proteins, or hypermethylation of regulatory elements has been suggested to be involved (48,50). Relevance of such knowledge lies in possible use of these pathways to rescue endogenous Epo production in anemic patients (51).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Renal interstitial mesenchymal cells, that is fibroblasts mainly in the cortex and pericytes mainly in the medulla, are the key producers of ECM (24,166,167). Like fibroblasts, renal pericytes, and in particular their mesenchymal stem cell subset, serve as progenitors of interstitial myofibroblasts in renal fibrogenesis (168) (Figure 3).…”

“…So far, myofibroblasts have been characterized by their prominent expression of a-smooth muscle actin (aSMA). With the development of novel markers, targeting tools, transgenic mice and cell isolation protocols, the functional and phenotypical heterogeneity and plasticity of these cells is becoming apparent (24,166,167,169). Using transgenic mice for example for the collagen1a1 promoter coupled with the reporter for translating ribosome affinity purification (TRAP), translational profiling of medullary pericytes was performed in healthy and fibrotic kidneys.…”