Subtherapeutic erythropoietin and insulin-like growth factor-1 correct the anemia of chronic renal failure in the mouse

Abstract

Chronic renal failure (CRF) is associated with a hyporegenerative anemia, which is caused primarily by inadequate production of erythropoietin (EPO) by the diseased kidneys and is responsive to exogenous EPO administration. Little is known about compensatory mechanisms that might supervene in anemia with low levels of EPO. Multiple investigations in vitro suggest an important role for insulin-like growth factor-1 (IGF-1) as well as EPO in erythropoiesis. Recently, both EPO and IGF-1 in vitro have been found to stimulate erythroid colony forming units in the mouse. However, no studies have examined the effect of IGF-1, singly and in combination with EPO, in CRF in vivo. This study examined mice with surgically-induced renal failure of six weeks duration that were treated for three weeks with the combination of subtherapeutic doses of both EPO and IGF-1. The single administration of each cytokine caused no significant change in hemoglobin in all CRF mice. In marked contrast the combined administration of the two cytokines produced a striking rise in hemoglobin, resulting in anemia correction in the majority of animals. The response to the combination therapy was comparable to the maximal response obtained with a single EPO dose (10 U) in a dose-finding study. Although the data are limited to utilizing one dose of each cytokine and one preparation of IGF-1, the large increase in hemoglobin observed with the combination therapy indicates that these two cytokines work in concert to stimulate erythroid precursors in CRF. In addition, untreated CRF mice showed markedly increased serum levels of low molecular weight binding proteins for IGF-1, potentially reducing the bioavailability of IGF-1. These findings taken together suggest that the anemia of CRF may represent both an EPO and a functional IGF-1 deficient state.

Erythropoietin Delivery by Genetically Engineered Bone Marrow Stromal Cells for Correction of Anemia in Mice with Chronic Renal Failure

“…Moreover, this model of CRF with anemia has been described to induce in mice the development of a constellation of other abnormalities also noted in humans with CRF (18 -20). In this well-characterized murine model, the anemia was reported to respond to rhEpo in a dose-dependent manner (18,19).…”

Mimicry of erythropoietin by a nonpeptide molecule

“…In humans, the most prevalent form of anemia is associated with kidney failure (7). At present, the only treatment for this form of anemia is administration of recombinant EPO via subcutaneous or intravenous injection (8)(9)(10). The use of recombinant EPO has significantly improved the quality of life of these patients; however, this treatment requires repeated administration of recombinant protein, which is both inconvenient and expensive.…”

Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia

“…MSC-IGF coimplantation significantly increased the plasma EPO levels of animals receiving MSC-EPO, but plasma IGF-I levels were not increased in mice receiving MSC-IGF alone compared with mice receiving MSC null. It is therefore clear that the difference in hematocrit was due to a local interaction between MSC-IGF and MSC-EPO within the implant, rather than a synergistic stimulation of erythroid progenitor development in the bone marrow, as described by Brox et al (7). Supporting this contention, our study adds to previous work reporting IGF-IR expression by murine MSC (9,18,42) and goes on to demonstrate that the IGF-IR is capable of inducing the dose-dependent phosphorylation of downstream effectors and modulating apoptosis in vitro.…”

“…In addition, it has been shown that murine and human bone marrow stromal cells express the IGF-I receptor (IGF-IR) (9,18,42), suggesting that murine MSC are likely to be responsive to IGF-I stimulation. IGF-I has long been known to stimulate erythroid progenitor development (4,26,36) and has been shown to synergistically increase hematocrit in mice with CKD-associated anemia when used in conjunction with EPO (7). We therefore hypothesized that IGF-I secretion by genemodified MSC (MSC-IGF) within a subcutaneous implant could serve as a protective microenvironment providing paracrine support to MSC-EPO, leading to improved long-term delivery of EPO for the treatment of renal anemia.…”