Abstract-The (pro)renin receptor ([P]RR) is a transmembrane protein that binds both renin and prorenin with high affinity, increasing the catalytic cleavage of angiotensinogen and signaling intracellularly through mitogen-activated protein kinase activation. Although initially reported as having no homology with any known membrane protein, other studies have suggested that the (P)RR is an accessory protein, named ATP6ap2, that associates with the vacuolar H ϩ -ATPase, a key mediator of final urinary acidification. Using in situ hybridization, immunohistochemistry, and electron microscopy, together with serial sections stained with nephron segment-specific markers, we found that (P)RR mRNA and protein were predominantly expressed in collecting ducts and in the distal nephron. Within collecting ducts, the (P)RR was most abundant in microvilli at the apical surface of A-type intercalated cells. Dual-staining immunofluorescence demonstrated colocalization of the (P)RR with the B1/2 subunit of the vacuolar H ϩ -ATPase, the ion exchanger that secretes H ϩ ions into the urinary space and that associates with an accessory subunit homologous to the (P)RR. In collecting duct/distal tubule lineage Madin-Darby canine kidney cells, extracellular signal-regulated kinase 1/2 phosphorylation, induced by either renin or prorenin, was attenuated by the selective vacuolar H ϩ -ATPase inhibitor bafilomycin. The predominant expression of the (P)RR at the apex of acid-secreting cells in the collecting duct, along with its colocalization and homology with an accessory protein of the vacuolar H ϩ -ATPase, suggests that the (P)RR may function primarily in distal nephron H ϩ transport, recently noted to be, at least in part, an angiotensin II-dependent phenomenon. Key Words: (pro)renin receptor Ⅲ intercalated cell Ⅲ vacuolar H ϩ -ATPase Ⅲ ATP6ap2 Ⅲ prorenin Ⅲ renin-angiotensin system Ⅲ bafilomycin A little more than a decade ago, the binding characteristics and activity of a specific renin receptor in cultured mesangial cells were reported. 1 This was followed in 2002 by the identification of an apparently novel, 350 amino acid, single-transmembrane protein that binds both renin and prorenin with high affinity. 2 Ligand binding to this (pro)renin receptor ([P]RR) induced a 4-fold increase in the catalytic cleavage of angiotensinogen, as well as stimulating intracellular signaling, with activation of mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) 1/2 2 and induction of transforming growth factor-␤ expression. 3 The existence of a (P)RR not only expanded our understanding of the physiology of the renin-angiotensin system (RAS) but also provided insight into the potential pathogenetic role of prorenin, the enzymatically inactive zymogen that is elevated in disease states, eg, diabetes mellitus, where it predicts the subsequent development of nephropathy and retinopathy. 4 Given its localization to the mesangium, its actions in augmenting local angiotensin II production, and its ability to increase mesangial tr...

In the Chx10-null ocular retardation (or J ) mouse, retinal progenitor cell (RPC) proliferation is impaired, and bipolar neurons, a late born cell type, fail to differentiate. It is unclear whether Chx10 is required to maintain proliferation throughout retinogenesis or whether the bipolar cell defect is an indirect effect of growth arrest. We show that Chx10 is dispensable for late-stage RPC proliferation but is essential to promote bipolar cell genesis in place of rods. Ectopic Chx10 expression drove bipolar instead of rod cell differentiation without affecting division. Converting Chx10 to an activator impaired bipolar cell differentiation, implying that repression is important for Chx10 activity. In the Chx10 null or J retina, only a small fraction of cells expressing mutated Chx10 mRNA were rods, but this fraction increased after p27 Kip1 inactivation, which partially rescues proliferation. Most significantly, acute Chx10 knockdown in the postnatal retina promoted rods in place of bipolar neurons without affecting division. Thus, Chx10 directly controls bipolar cell genesis by inhibiting rod differentiation independent of its temporally limited early effect on RPC proliferation.CVC domain ͉ homeobox ͉ homeodomain ͉ short-hairpin RNA

BackgroundMost forms of chronic kidney disease are characterized by progressive renal and cardiac fibrosis leading to dysfunction. Preliminary evidence suggests that various bone marrow-derived cell populations have antifibrotic effects. In exploring the therapeutic potential of bone marrow derived cells in chronic cardio-renal disease, we examined the anti-fibrotic effects of bone marrow-derived culture modified cells (CMCs) and stromal cells (SCs).Methodology/Principal Findings In vitro, CMC-conditioned medium, but not SC-conditioned medium, inhibited fibroblast collagen production and cell signalling in response to transforming growth factor-ß. The antifibrotic effects of CMCs and SCs were then evaluated in the 5/6 nephrectomy model of chronic cardio-renal disease. While intravascular infusion of 106 SCs had no effect, 106 CMCs reduced renal fibrosis compared to saline in the glomeruli (glomerulosclerosis index: 0.8±0.1 v 1.9±0.2 arbitrary units) and the tubulointersitium (% area type IV collagen: 1.2±0.3 v 8.4±2.0, p<0.05 for both). Similarly, 106 CMCs reduced cardiac fibrosis compared to saline (% area stained with picrosirius red: 3.2±0.3 v 5.1±0.4, p<0.05), whereas 106 SCs had no effect. Structural changes induced by CMC therapy were accompanied by improved function, as reflected by reductions in plasma creatinine (58±3 v 81±11 µmol/L), urinary protein excretion (9×/÷1 v 64×/÷1 mg/day), and diastolic cardiac stiffness (left ventricular end-diastolic pressure-volume relationship: 0.030±0.003 v 0.058±0.011 mm Hg/µL, p<0.05 for all). Despite substantial improvements in structure and function, only rare CMCs were present in the kidney and heart, whereas abundant CMCs were detected in the liver and spleen.Conclusions/SignificanceTogether, these findings provide the first evidence suggesting that CMCs, but not SCs, exert a protective action in cardio-renal disease and that these effects may be mediated by the secretion of diffusible anti-fibrotic factor(s).