Feature Review
Partial Epithelial-to-Mesenchymal Transition and Other New Mechanisms of Kidney Fibrosis

https://doi.org/10.1016/j.tem.2016.06.004Get rights and content

Trends

Myofibroblast accumulation in kidney fibrosis is due to the proliferation of the resident interstitial fibroblasts and the differentiation from bone marrow progenitors, tubular epithelial cells, and peritubular endothelial cells.

Non-reversible epigenetic modifications, such as methylation, sustain and perpetuate the activated state of interstitial myofibroblasts.

EMT contributes to the loss of functional parenchyma by impairing the ability of tubular epithelial cells to proliferate and by compromising their functional properties.

Injured tubular epithelial cells display dramatic metabolic rearrangements, such as a profound suppression of fatty acid oxidation, which highly impacts on the regeneration capacity and fibrogenesis.

Macrophages, lymphocytes, dendritic cells and mast cells are key players in mediating inflammation and immune response in kidney fibrosis. The balance between their pro-fibrogenic and anti-inflammatory functions likely determines the final fibrotic outcome.

Kidney fibrosis is the unavoidable consequence of chronic kidney disease irrespective of the primary underlying insult. It is a complex phenomenon governed by the interplay between different cellular components and intricate networks of signaling pathways, which together lead to loss of renal functionality and replacement of kidney parenchyma with scar tissue. An immense effort has recently been made to understand the molecular and cellular mechanisms leading to kidney fibrosis. The cellular protagonists of this process include myofibroblasts, tubular epithelial cells, endothelial cells, and immune cells. We discuss here the most recent findings, including partial epithelial-to-mesenchymal transition (EMT), in the initiation and progression of tissue fibrosis and chronic kidney disease (CKD). A deep understanding of these mechanisms will allow the development of effective therapies.

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

References (130)

  • J. Li

    Rictor/mTORC2 protects against cisplatin-induced tubular cell death and acute kidney injury

    Kidney Int.

    (2014)
  • H. Tao

    MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats

    Toxicology

    (2011)
  • B. Tampe

    Induction of Tet3-dependent epigenetic remodeling by low-dose hydralazine attenuates progression of chronic kidney disease

    EBioMedicine

    (2015)
  • B. Kaissling

    Renal epithelial injury and fibrosis

    Biochim. Biophys. Acta

    (2013)
  • M.J. Hiatt

    Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

    Lab Invest.

    (2013)
  • B.D. Humphreys

    Intrinsic epithelial cells repair the kidney after injury

    Cell Stem Cell

    (2008)
  • S. Kumar

    Sox9 activation highlights a cellular pathway of renal repair in the acutely injured mammalian kidney

    Cell Rep.

    (2015)
  • H.M. Kang

    Sox9-positive progenitor cells play a key role in renal tubule epithelial regeneration in mice

    Cell Rep.

    (2016)
  • R.H. Jenkins

    miR-192 induces G2/M growth arrest in aristolochic acid nephropathy

    Am. J. Pathol.

    (2014)
  • J. Tang

    Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury

    Am. J. Pathol.

    (2013)
  • I. Grgic

    Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis

    Kidney Int.

    (2012)
  • C.F. Wu

    Transforming growth factor beta-1 stimulates profibrotic epithelial signaling to activate pericyte–myofibroblast transition in obstructive kidney fibrosis

    Am. J. Pathol.

    (2013)
  • J. Megyesi

    Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure

    Kidney Int.

    (2001)
  • M. Zeisberg

    Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition

    J. Biol. Chem.

    (2007)
  • S.N. Flier

    Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis

    J. Biol. Chem.

    (2010)
  • L. Li

    Autophagy is a component of epithelial cell fate in obstructive uropathy

    Am. J. Pathol.

    (2010)
  • M.P. Rastaldi

    Epithelial–mesenchymal transition of tubular epithelial cells in human renal biopsies

    Kidney Int.

    (2002)
  • M. Zeisberg

    Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney

    J. Biol. Chem.

    (2005)
  • M. Herman-Edelstein

    Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy

    J. Lipid Res.

    (2014)
  • A.E. Decleves

    Regulation of lipid accumulation by AMP-activated kinase in high fat diet-induced kidney injury

    Kidney Int.

    (2014)
  • M. Jiang

    Autophagy in proximal tubules protects against acute kidney injury

    Kidney Int.

    (2012)
  • S.I. Kim

    Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1

    J. Biol. Chem.

    (2012)
  • D.A. Ferenbach et al.

    Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD

    Nat. Rev. Nephrol.

    (2015)
  • V.S. LeBleu

    Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis

    Nat. Med.

    (2013)
  • L.L. Falke

    Diverse origins of the myofibroblast-implications for kidney fibrosis

    Nat. Rev. Nephrol.

    (2015)
  • V.S. LeBleu

    Origin and function of myofibroblasts in kidney fibrosis

    Nat. Med.

    (2013)
  • N.C. Henderson

    Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs

    Nat. Med.

    (2013)
  • N. Asada

    Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice

    J. Clin. Invest.

    (2011)
  • W.A. Border

    Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1

    Nature

    (1990)
  • W.A. Border

    Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease

    Nature

    (1992)
  • F.T. Borges

    TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis

    J. Am. Soc. Nephrol.

    (2013)
  • W. Lieberthal et al.

    Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications

    Am. J. Physiol. Renal. Physiol.

    (2012)
  • G. Canaud

    Inhibition of the mTORC pathway in the antiphospholipid syndrome

    N. Engl. J. Med.

    (2014)
  • G. Chen

    Rapamycin ameliorates kidney fibrosis by inhibiting the activation of mTOR signaling in interstitial macrophages and myofibroblasts

    PLoS ONE

    (2010)
  • L. Jiang

    Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis

    J. Am. Soc. Nephrol.

    (2013)
  • A. Goc

    TGFbeta- and bleomycin-induced extracellular matrix synthesis is mediated through Akt and mammalian target of rapamycin (mTOR)

    J. Cell Physiol.

    (2011)
  • W. Yin

    Mammalian target of rapamycin mediates kidney injury molecule 1-dependent tubule injury in a surrogate model

    J. Am. Soc. Nephrol.

    (2015)
  • H. Ding

    Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis

    J. Am. Soc. Nephrol.

    (2012)
  • D. Zhou

    Sonic hedgehog is a novel tubule-derived growth factor for interstitial fibroblasts after kidney injury

    J. Am. Soc. Nephrol.

    (2014)
  • W. Bechtel

    Methylation determines fibroblast activation and fibrogenesis in the kidney

    Nat. Med.

    (2010)
  • Cited by (0)

    View full text