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Cells of human, rat, and mouse kidney express functional erythropoietin receptors. Background. Erythropoietin (EPO), secreted by fibroblast-like cells in the renal interstitium, controls erythropoiesis by regulating the survival, proliferation, and differentiation of erythroid progenitor cells. We examined whether renal cells that are exposed to EPO express EPO receptors (EPO-R) through which analogous cytokine responses might be elicited. Methods. Normal human and rat kidney tissue and defined cell lines of human, rat, and mouse kidney were screened, using reverse transcription-polymerase chain reaction, nucleotide sequencing, ligand binding, and Western blotting, for the expression of EPO-R. EPO’s effects on DNA synthesis and cell proliferation were also examined. Results. EPO-R transcripts were readily detected in cortex, medulla, and papilla of human and rat kidney, in mesangial (human, rat), proximal tubular (human, mouse), and medullary collecting duct cells (human). Nucleotide sequences of EPO-R cDNAs from renal cells were identical to those of erythroid precursor cells. Specific 125I-EPO binding revealed a single class of high- to intermediate-affinity EPO-Rs in each tested cell line (kD 96 pm to 1.4 nm; Bmax 0.3 to 7.0 fmol/mg protein). Western blots of murine proximal tubular cell membranes revealed an EPO-R protein of approximately 68 kDa. EPO stimulated DNA synthesis and cell proliferation dose dependently. Conclusion. This is the first direct demonstration, to our knowledge, that renal cells possess EPO-Rs through which EPO stimulates mitogenesis. This suggests currently unrecognized cytokine functions for EPO in the kidney, which may prove beneficial in the repair of an injured kidney while being potentially detrimental in renal malignancies. [ABSTRACT FROM AUTHOR]

Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their administration into the suprarenal aorta after reflow significantly protected renal function and hastened repair, mediated by complex antiapoptotic, mitogenic, anti-inflammatory, and immune modulating actions that were not elicited by isogeneic fibroblasts. Infused mesenchymal stem cells, recruited to renal sites of injury, did not significantly differentiate into target cells but rather disappeared from kidneys and other organs within 72 h. Furthermore, at 3 months, compared with vehicle-treated controls, renal function was well preserved and interstitial fibrosis was absent. These preclinical data served as the scientific basis for a recently completed Phase I Clinical Trial (http://www.clinicaltrials.gov; # NCT00733876), in which patients at high risk for cardiac surgery-associated AKI were treated with allogeneic mesenchymal stem cells. Until now, MSC therapy in the study subjects has been safe, and none of the patients has developed postoperative AKI or subsequent loss of renal function, suggesting that this novel form of therapy may have promise in this group of high-risk patients, which will be further investigated in a Phase II Trial. [ABSTRACT FROM AUTHOR]

Erythropoietin stimulates proliferation of human renal carcinoma cells. Background. We reported recently that normal human, rat, and mouse tubular cells express authentic erythropoietin-receptors (EPO-R) through which EPO stimulates mitogenesis. The present study examines whether EPO could elicit such a proliferative and thereby potentially detrimental response in cells of human renal-cell carcinoma (RCC). Methods. Nephrectomy samples were screened from patients with RCC (one chromophilic, two clear cell) as well as cell lines of human (Caki-2, 786-0) and mouse (RAG) renal adenocarcinomas for expression of EPO-R transcripts and protein. Cells were further tested for specific 125 I-EPO binding and mitogenic response to EPO. Results. Authentic EPO-R transcripts and protein (approximately 72 kD) were detected in renal tumors and cell lines. Tumors showed low-level EPO expression, while cell lines did not. In cells, specific 125 I-EPO binding to a single class of EPO-R (apparent Kd 1.3 to 1.4 nmol/L, Bmax 2.2 to 2.6 fmol/mg protein) was observed. EPO stimulated cell proliferation dose dependently, and the individual mitogenic effects of either EPO or 10% newborn calf serum were markedly amplified when both were coadministered. Conclusion. These data are the first to demonstrate, to our knowledge, that human RCCs express EPO-R message and protein and that receptor activation stimulates their proliferation in vitro. If these mitogenic effects of EPO are also operative in patients with RCC, endogenous EPO or its administration for the treatment of anemia could potentially hasten proliferation of renocellular malignancies. [ABSTRACT FROM AUTHOR]

Because pharmacological interventions for the treatment of acute kidney injury (AKI) have remained ineffective, cell-based therapies have been developed. Marrow stromal cells have been found to be safe and potentially effective in study subjects. Jung et al. demonstrate that macrophages made to overexpress anti-inflammatory interleukin-10 protect rats with AKI through iron-mediated upregulation of lipocalin-2 and its receptors, eliciting both anti-inflammatory and proliferative responses. These data further advance our understanding of cell-based therapies for AKI. [ABSTRACT FROM AUTHOR]

Both the homing of hematopoietic stem cells (HSCs) to the bone marrow and their engraftment in recipients of bone marrow transplants are primarily mediated by the chemokine stromal-derived factor-1 (SDF-1) or CXCL12, which activates CXCR4, its cognate receptor on HSCs. We showed that the recruitment and temporary attachment of CXCR4-expressing cells, such as HSCs and a fraction of mesenchymal stem cells (MSCs), to the kidney, following ischemia/reperfusion acute kidney injury, are similarly mediated by robustly upregulated SDF-1 in the kidney, indicating that such organ injury appears to lead to the transient expression of a facultative stem cell niche. This SDF-1 response of the injured kidney facilitates both the mobilization from the bone marrow and homing of precursor cells, and other CXCR4-expressing cells such as administered MSCs, to the kidney, where they aid in its protection and repair. Similar responses have been observed subsequent to the injury of other solid organs such as the heart, liver, and brain. [ABSTRACT FROM AUTHOR]

Novel urinary biomarkers for the early, sensitive, and specific diagnosis of acute kidney injury (AKI) show promise for the improved management of patients with this treatment-resistant complication. Several biomarkers (Kim-1, lipocalin-2, osteopontin, gluthathione S-transferases) that were tested by Rouse et al. during gentamicin-induced AKI and its recovery possess renoprotective activities, capabilities that may guide the development of novel interventions. However, despite the increased commercial availability of biomarkers, effective therapies for clinical AKI await discovery. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (mSCs) are presently studied for the prophylaxis and therapy of a variety of diseases such as acute graft-versus-host disease after allogeneic stem cell transplantation, cardiac indications, bone degeneration, Crohn's disease, and organ rejection, as well as prevention of acute renal failure in high-risk situations. mSCs appear to function through paracrine mechanisms that exert immunosuppressive, anti-inflammatory, anti-apoptotic, mitogenic, and other organ-protective and repair-stimulating actions. mSCs are either cultured in the presence of fetal calf serum (FCS) or platelet lysate (PL). PL lysate-generated mSCs exhibit faster doubling times, different gene expression profiles, and more potent immunosuppressive activity compared with FSC-generated mSCs. The utility of mSCs in the treatment of chronic inflammatory diseases is being evaluated in prospective studies. [ABSTRACT FROM AUTHOR]

Background. Adult stem cells are promising for the development of novel therapies in regenerative medicine. Acute renal failure (ARF) remains a frequent clinical complication, associated with an unacceptably high mortality rate, in large part due to the ineffectiveness of currently available therapies. The aim of this study was, therefore, to evaluate the therapeutic effectiveness of bone marrow–derived mesenchymal stem cells in a rat model of ischemia/reperfusion (I/R) ARF. Methods. We used a common I/R model in rats to induce ARF by clamping both renal pedicles for 40 minutes. Mesenchymal stem cells were iron-dextran–labeled for in vivo tracking studies by magnetic resonance imaging (MRI) and kidneys were imaged for mesenchymal stem cells immediately after infusion and at day 3 after ARF. Renal injury was scored on day 3 and cells were additionally tracked by Prussian blue staining. Results. We show in I/R-induced ARF in rats, modeling the most common form of clinical ARF, that infusion of mesenchymal stem cells enhances recovery of renal function. Mesenchymal stem cells were found to be located in the kidney cortex after injection, as demonstrated by MRI. Mesenchymal stem cells–treated animals had both significantly better renal function on days 2 and 3 and better injury scores at day 3 after ARF. Histologically, mesenchymal stem cells were predominantly located in glomerular capillaries, while tubules showed no iron labeling, indicating absent tubular transdifferentiation. Conclusion. We conclude that the highly renoprotective capacity of mesenchymal stem cells opens the possibility for a cell-based paradigm shift in the treatment of I/R ARF. [ABSTRACT FROM AUTHOR]

Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Background. Stem cell and leukocyte migration during homeostasis and inflammation is regulated by a number of chemokines. Stromal cell–derived factor-1 (SDF-1) and its receptor CXCR4 are important mediators of leukocyte homeostasis. The postischemic kidney has been shown to recruit different leukocyte populations, including bone marrow–derived stem cells. Therefore, we investigated the SDF-1/CXCR4 system in the kidney after ischemic acute renal failure (ARF). Methods. We used immunohistochemistry, in situ hybridization, enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect SDF-1 and CXCR4 in the normal kidney and the kidney after ischemia/reperfusion (I/R) ARF. Mobilization was assessed by flow cytometry for CD34 and colony assays. Results. We show that SDF-1 is expressed in the normal mouse kidney and tubular cells express CXCR4. SDF-1 expression in the kidney increases after I/R induced ARF and decreases in the bone marrow, thereby reversing the normal gradient between bone marrow and the periphery. This causes mobilization of CD34-positive cells into the circulation and their subsequent homing to the kidney with ARF. In vitro and in vivo chemotaxis of bone marrow cells toward damaged kidney epithelium is reversibly inhibited by anti-CXCR4 antibodies. Conclusion. Our data show that renal SDF-1 is a currently unrecognized mediator of homing to and migration of CXCR4 expressing cells in the injured kidney. Because certain cells that express CXCR4 may have renoprotective effects, our results suggest that SDF-1 may be a major signal involved in kidney repair. [ABSTRACT FROM AUTHOR]