Trends in Endocrinology & Metabolism
Feature ReviewPartial Epithelial-to-Mesenchymal Transition and Other New Mechanisms of Kidney Fibrosis
Section snippets
Unraveling the Mediators of Kidney Fibrosis
Chronic kidney disease (CKD, see Glossary) has an estimated worldwide prevalence of 8–16%. It poses a major challenge because CKD can lead to end-stage renal disease (ESRD), requiring dialysis therapy or kidney transplantation to circumvent death. ESRD has a huge cost impact for healthcare systems. In the USA alone, treatment of CKD has an annual cost of $48 billion [1]. Owing to this high health cost and the high mortality from untreated kidney failure, great attention and massive effort have
Origin
The use of genetically engineered mouse models to track myofibroblasts has clearly shown that α-smooth muscle actin-positive (αSMA+) myofibroblasts accumulate in the interstitium of fibrotic kidneys [3]. However, the origin of this myofibroblast population has long been debated and there are discrepancies that likely reflect the heterogeneity of the mouse models used to identify the source of this cell population [4]. Cellular contributors that have been traditionally proposed to give rise to
Tubular Epithelial Cells
Considerable work has been done on elucidating the mechanisms activated in TECs in response to injury and on understanding whether this response is the driving force for the perpetuation of the fibrotic process [34]. Cell cycle arrest, EMT, metabolic alterations and autophagy have been designated as hallmarks of injured TECs. Although the majority of these studies focused on the cortical region and the proximal segment of the renal nephron, which appeared to be the most highly affected by
Immune Cells
Fibrosis is a disease of inflammation and immune infiltration, and both play a significant role in the pathogenesis of CKD. The immune milieu comprises macrophages, lymphocytes, dendritic cells (DCs), and mast cells. Macrophages have been considered to be the major drivers of inflammation and fibrosis in kidney disease because of their capacity to synthesize and secrete several different molecules, such as growth factors, enzymes, and matrix proteins, which promote and sustain the fibrogenic
Concluding Remarks and Future Perspectives
Kidney fibrosis is a multifactorial and dynamic disease. It involves all cell types present in the renal tissue as well as in cells of extrarenal origin. Immense advances have been achieved in understanding the contributions of the different sources of myofibroblasts, the mechanisms underlying tubular atrophy, the impact on the peritubular vasculature, and the involvement of the immune system. The picture emerging from these findings shows that kidney fibrosis is a disease of heterogeneity and
Acknowledgments
Research work in the laboratory of R.K. is supported by the Cancer Prevention and Research Institute of Texas and the MD Anderson Cancer Center. Research work in the laboratory of M.Z. is supported by the Deutsche Forschungsgemeinschaft (ZE523/2-1 and ZE523/4-1). We apologize to any authors whose work might have been omitted owing to space limitations imposed on this review.
Glossary
- Acute kidney injury (AKI)
- a temporary failure of kidney functionality, typically caused by decreased blood flow, toxic exposure, or obstruction. As the original insult is removed, repair and resolution occur. Failure of a complete repair in AKI highly predisposes a patient to progress into chronic kidney disease.
- Chronic kidney disease (CKD)
- a condition characterized by the progressive loss of the kidney functionality. It is clinically defined by reduced glomerular filtration rate and increased
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