Current Gene Therapy - Volume 17, Issue 6, 2017

In deceased donors, Ischemia/Reperfusion Injury (IRI) is an important cause of allograft dysfunction. Prolonged cold and warm ischemia time leads to a high risk of early post-transplant complications, including acute and chronic rejection. Ischemia not only up-regulates inflammatory cytokines and chemokines, but also enhances the expression of MHC-class II and adhesion molecules on epithelial and dendritic cells. Moreover, the Danger Associated Molecular Patterns (DAMPs) released from stressed or dying cells, not only cause or amplify tissue inflammation and trigger tissue repair in response to IRI, but also act as adjuvants that enhance DC maturation and potentiate the adaptive immune response. In this review, we will also discuss about whether donor or recipient DCs are more important in the process of ischemia enhanced acute rejection.

Acute kidney injury has been a tough complex with increased mortality and morbidity. Inflammatory responses, including innate and adaptive immune responses, involve in the initiation and development of acute kidney injury, especially under the ischemic circumstances. Tubular cells and distinct immune cell subgroups play a critical role in the pathogenesis of inflammation. Current gene therapies show their benefits in renal repair. Here, we reviewed the renal inflammatory infiltration, inflammatory mediators, oxidative stress and potential signaling pathways, which give rise to the kidney diseases, in the mechanism of acute kidney injury. Recent studies showed diverse insights in understanding the pathophysiological process of inflammation related renal injury and provided novel clinical targets for ameliorating acute kidney injury by balancing the facilitation of repairing and prevention of impairing. Interestingly, antisense oligonucleotides of target sequence, local electransfering on solid organ and adenovirus-mediated certain gene overexpression have been promising strategies in alleviating acute kidney injury.

Renal Ischemia-Reperfusion Injury (IRI) is one of the main causes of Acute Kidney Injury (AKI), and may lead to chronic kidney disease. The high mortality rate of AKI has not changed in the last 5 decades due to non-recognition, nephrotoxin exposure, delayed diagnosis and lack of specific intervention. Complement activation plays important roles in IRI-induced AKI because of its association with immunity, inflammation, cell death and tissue repair. Nevertheless, the role of complement properdin, the sole positive regulator of the alternative pathway, in IRI-induced AKI has not been well defined. This review evaluates the dynamic changes and underlying mechanisms of complement activation with a focus on properdin in both in vitro and in vivo models challenged by hypoxia/ reoxygenation and renal IRI. The multiple actions of properdin associated with HMGB1 and caspase-3, apoptosis and inflammation mediators, are discussed in the context of immunity, injury and repair at both the early and later stages of AKI. The complement activation-independent role of properdin and the effect of modulating properdin with or without genotype alteration are also addressed. Taking together, these might provide new mechanistic insights that potentially benefit timely diagnosis and specific intervention of IRI-induced AKI.

Diabetic Kidney Disease (DKD) is one of the major complications of Diabetes Mellitus (DM) and is currently the most common cause of End-Stage Renal Disease (ESRD) worldwide. Traditionally, DKD is considered a disease which has nothing to do with the immune system, and the pathogenesis is mainly characterized to be metabolic disturbance. Recent growing evidence indicates immunologic and inflammatory mechanisms in the development and progression of DKD. This overview of macrophages, dendritic cells, T lymphocytes, B lymphocytes, neutrophils and mast cells is closely involved in the pathologic process of DKD, with more emphasis on the leucocyte accumulation and related molecular mechanisms. Moreover, the potential contributions of these immune cells to renal injury will also be discussed. Specifically, these findings help to identify new potential therapeutic targets of DKD. Future preclinical and clinical studies might translate these exciting findings into clinical applications.

Allograft loss remains a severe clinical problem after kidney transplantation. The molecular mechanism of graft loss is a complex process involving T and/or B cell activation, inflammation responses, autophagy and apoptosis. Since these pathways are involved in immune responses in kidney transplant rejection, application of genetic interference to inhibit specific pathways could present an effective targeted gene therapy method. Recent studies have successfully attempted to use gene therapy to target the key molecules involved in immune responses during transplantation. This strategy has the potential to silence target genes associated with a variety of diseases, including those that trigger allograft loss following organ transplantation. In this review, we have discussed evidence of the clinical applicability of gene therapy in kidney transplantation based on known associations between kidney diseases and genes participating in the underlying mechanisms. The molecules contributing to immune responses and inflammatory injury are further highlighted as potential targets in future clinical therapy for renal transplantation.

The fractalkine receptor chemokine (C-X3-C motif) receptor 1 (CX3CR1) and its highly selective ligand CX3CL1 mediate chemotaxis and adhesion of immune cells, which are involved in the pathogenesis and progression of numerous inflammatory disorders and malignancies. The CX3CL1/CX3CR1 axis has recently drawn attention as a potential therapeutic target because it is involved in the ontogeny, homeostatic migration, or colonization of renal phagocytes. We performed a Medline/PubMed search to detect recently published studies that explored the relationship between the CX3CL1/CX3CR1 axis and renal diseases and disorders, including diabetic nephropathy, renal allograft rejection, infectious renal diseases, IgA nephropathy, fibrotic kidney disease, lupus nephritis and glomerulonephritis, acute kidney injury and renal carcinoma. Most studies demonstrated its role in promoting renal pathopoiesis; however, several recent studies showed that the CX3CL1/CX3CR1 axis could also reduce renal pathopoiesis. Thus, the CX3CL1/CX3CR1 axis is now considered to be a double-edged sword that could provide novel perspectives into the pathogenesis and treatment of renal diseases and disorders.

Acute Kidney Injury (AKI) is a common syndrome in the clinic and has become a worldwide public health problem. Renal Ischemia-Reperfusion Injury (IRI) is the most common cause of AKI. So far, effective treatment is still lacking for renal IRI, resulting in a high mortality rate of AKI. Mesenchymal Stem Cells (MSCs), considered as a promising candidate for tissue repair and regenerative medicine have aroused an increasing concern in recent years for the capacity of self-renewal and multi-lineage differentiation. MSC-based therapy has drawn wide attention for its therapeutic potential in renal IRI. The administrated MSCs can alleviate the renal IRI and improve the renal function for its anti-inflammatory, immunomodulation properties. MSCs preferentially migrate into injured sites to play the role of tissue repair. Furthermore, MSCs can modify the microenvironment to promote the recovery of damaged renal tubular cells via paracrine factors. However, the poor kidney-directional homing and poor survival under ischemia environment have limited their beneficial effects. Genetic modification is an effective approach to increase the therapeutic action of MSCs. MSCs are modified with exogenous genes to enhance their innate properties. Here we review the current knowledge of gene-modified MSCs, their biological characteristics and applications in renal IRI.

Regulatory T (Treg) cells are a kind of immunosuppression cells, which have been used to treat autoimmune diseases and induce allograft tolerance in clinical trials. While Treg cells based therapy is a promising treatment for kidney diseases and an emerging concept for tolerance induction in renal transplantation, a better understanding of the functions and biology of Treg cells is needed to be able to optimally exploit them. Epigenetics regulation, which refers to potentially heritable alterations in gene expression without underlying changes of the nucleotide sequence, plays an important role in Treg cells induction and maintenance. The expression of Foxp3, the key factor of Treg cells, is regulated by DNA methylation, histone modification and post-transcriptionally modification. Herein, we review the current understanding of Treg cells in kidney diseases and transplantation, and discuss the epigenetic regulation of Treg cells.