The use of stem cells has enabled the successful generation of simple organs. However, anatomically complicated organs such as the kidney have proven more refractory to stem-cell-based regenerative techniques. Given the limits of allogenic organ transplantation, an ultimate therapeutic solution is to establish self-organs from autologous stem cells and transplant them as syngrafts back into donor patients. To this end, we have striven to establish an in vitro organ factory to build up complex organ structures from autologous adult stem cells by using the kidney as a target organ. Cultivation of human mesenchymal stem cells in growing rodent embryos enables their differentiation within a spatially and temporally appropriate developmental milieu, facilitating the first step of nephrogenesis. We show that a combination of whole-embryo culture, followed by organ culture, encourages exogenous human mesenchymal stem cells to differentiate and contribute to functional complex structures of the new kidney.organogenesis ͉ regeneration
Glomerular mesangial cells express matrix metalloproteinase-9 (MMP-9) in response to the proinflammatory cytokine interleukin-1 beta (IL-1 beta). To elucidate the signal transduction systems involved, we focused on the role of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), since the 5'-flanking region of MMP-9 gene contains binding sequences for these transacting molecules. In rat mesangial cells treated with an inhibitor of NF-kappa B, pyrrolidine dithiocarbamate, induction of MMP-9 by IL-1 beta was suppressed at both mRNA and protein levels. Mesangial cells stably transfected with a transdominant negative mutant of NF-kappa B also showed blunted induction of MMP-9. Transient transfection study with a kappa B reporter plasmid revealed that IL-1 beta indeed activated the kappa B site and that pyrrolidine dithiocarbamate abolished this activation. These results suggest that IL-1 beta induced MMP-9 via the stimulation of NF-kappa B pathway. to examine whether tyrosine kinase is involved in this pathway, mesangial cells were stimulated by IL-1 beta in the presence of a tyrosine kinase inhibitor genistein. This inhibitor dose dependently suppressed the expression of MMP-9, as well as the activation of the kappa B site by IL-1 beta, indicating the involvement of tyrosine kinase in the stimulation of NF-kappa B. Because mesangial cells stimulated by IL-1 beta transiently expressed c-fos and c-jun nRNAs prior to the expression of MMP-9, the role of these genes in mediating the IL-1 beta response was further examined. Transfection of mesangial cells with a c-jun antisense cDNA and treatment with a pharmacological inhibitor of c-Jun/ AP-1, curcumin, revealed that the induction of c-Jun/AP-1 is essential for the expression of MMP-9 by IL-1 beta. Although protein kinase C (PKC) is regarded as a potential inducer of AP-1, stimulation of mesangial cells with phorbol 12-myristate 13-acetate failed to induce MMP-9. Similarly, depletion of intracellular PKC did not obviously affect the induction of MMP-9 by IL-1 beta. These findings demonstrate that dual operation of tyrosine kinase-mediated NF-kappa B stimulation and c-Jun/AP-1 activation is essential to the induction of MMP-9 by IL-1 beta in cultured mesangial cells.
BackgroundThe study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN).MethodsPatients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria.ResultsDuring 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01–8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission.ConclusionsThe results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.