TGF-β Signaling via TAK1 Pathway: Role in Kidney Fibrosis

In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. Emerging evidence shows a complex scheme of signaling networks that enable multifunctionality of TGF-β1 actions. Specific targeting of the TGF-β signaling pathway is seemingly critical and an attractive molecular therapeutic strategy. TGF-β1 signals through the interaction of type I and type II receptors to activate distinct intracellular pathways involving the Smad and the non-Smad. The Smad signaling axis is known as the canonical pathway induced by TGF-β1. Importantly, recent investigations have shown that TGF-β1 also induces various non-Smad signaling pathways. In this review, we focus on current insights into the mechanism and function of the Smad-independent signaling pathway via TGF-β-activated kinase 1 and its role in mediating the profibrotic effects of TGF-β1.     

Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Excessive TGF-β signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-β signaling on development of fibrosis, there is a lack of information on ablating TGF-β signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-β receptor knockout (TβRII^endo+/−) mice to explore whether curtailed TGF-β signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TβRII^endo+/+ mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TβRII^endo+/− mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TβRII^endo+/+ counterparts. In addition, partial deletion of TβRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-β–induced canonical Smad2 signaling was reduced in TβRII^+/− ECs; however, activin receptor-like kinase 1 (ALK1)–mediated Smad1/5 phosphorylation in TβRII^+/− ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TβRII^+/− ECs compared with TβRII^+/+ ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-β signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-β signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.     

Nitric Oxide Regulates Expression of Sonic Hedgehog and Hypoxia-Inducible Factor-1α in an Experimental Model of Kidney Ischemia-Reperfusion

This study was designed to determine the effect of L-arginine on hypoxia inducible factor alpha (HIF-1 α) and Sonic hedgehog (Shh) levels considered to be involved in the development of ischemia/reperfusion (I/R) injury. Unilaterally nephrectomized Sprague-Dawley rats were subjected to 60 minutes of left renal ischemia followed by 45 minutes of reperfusion. Group 1 were sham-operated animals; group 2, I-R/Untreated animals; and group 3, I-R/L-Arg-treated animals. Serum creatinine, blood urea nitrogen (BUN), and kidney malondialdehyde (MDA) levels were determined as well as examining the kidneys histologically. The treatment of rats with L-Arg produced a significant reduction in the levels of BUN, creatinine, MDA, and histopathological score compared to renal I/R groups. The Shh expression in the tubulus epithelia were intensely increased in the I-R/L-Arg group when compared to that of the Sham-control and the I-R/untreated groups. Additionally, the HIF-1α expression in the tubulus epithelia and the interstitial spaces were intensely increased in the I-R/L-Arg group. These findings suggest that NO reduces the renal dysfunction associated with I/R of the kidney and may act as a trigger to induce Shh and HIF-1 activity.     

Acute Antibody-Mediated Rejection by De Novo Anti-HLA-DPβ and -DPα Antibodies After Kidney Transplantation: A Case Report

The presence of isolated de novo anti-DP antibodies is uncommon, making it difficult to determine the impact of anti-DP antibodies on graft outcome. We describe a case of acute antibody-mediated rejection mediated by de novo donor-specific anti-HLA-DP antibodies. Furthermore, the generation of non–donor-specific anti-DP antibodies (NDSAs) detected in the patient's sera was investigated. An 18-year-old woman with pretransplant 0% panel-reactive antibody received kidney transplantation from a living donor. She experienced combined acute T-cell-mediated and antibody-mediated rejection at 15 months after transplantation. High resolution HLA typing of the donor and the patient revealed that they were mismatched at both DPB1 (DPB1*31:01) and DPA1 (DPA1*02:02) loci. The single antigen bead (SAB) testing of patient's sera revealed antibodies against donor's DPB1*31:01 and DPA1*02:02 alleles. Antibodies against several non–donor-specific DP antigens were also detected. No antibodies against other HLA class I and II antigens were detected. In order to explain the reactivity pattern of NDSAs, HLAMatchmaker program was used to identify immunizing eplets shared between donor alleles and reactive beads. The analysis showed 84DEAV, a DPB1 eplet, as a shared eplet found on DPB1*31:01 (mismatched donor allele) and on DPB1-reactive alleles in SAB assay. Additionally, 50RA, a DPA1 eplet, was identified as a shared eplet found on DPA1*02:02 (mismatched donor allele) and on DPA1-reactive alleles in SAB assay. This case highlights the clinical significance of HLA-DP antibodies. Furthermore, the generation of NDSA anti-DP antibodies by epitope sharing underscores the importance of HLA-DP epitope matching in kidney transplantation.     

The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells

Epithelial-mesenchymal transition (EMT) is an essential process that drives polarized, immotile mammary epithelial cells (MECs) to acquire apolar, highly migratory fibroblastoid-like features. EMT is an indispensable process that is associated with normal tissue development and organogenesis, as well as with tissue remodeling and wound healing. In stark contrast, inappropriate reactivation of EMT readily contributes to the development of a variety of human pathologies, particularly those associated with tissue fibrosis and cancer cell invasion and metastasis, including that by breast cancer cells. Although metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby EMT mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis, and EMT. In addition, TGF-β also functions as a powerful tumor suppressor in MECs, whose neoplastic development ultimately converts TGF-β into an oncogenic cytokine in aggressive late-stage mammary tumors. Recent findings have implicated the process of EMT in mediating the functional conversion of TGF-β during breast cancer progression, suggesting that the chemotherapeutic targeting of EMT induced by TGF-β may offer new inroads in ameliorating metastatic disease in breast cancer patients. Here we review the molecular, cellular, and microenvironmental factors that contribute to the pathophysiological activities of TGF-β during its regulation of EMT in normal and malignant MECs.