title: Apoptosis, fibrosis and senescence.
abstract: Fibrosis is a major hallmark of progressive kidney disease. The cellular mechanisms that lead to kidney tissue fibrosis are complex and include, for example, increased inflammation, increased oxidative stress, and proximal tubule cell death in the form of apoptosis or senescence. Recent studies have identified TWEAK, a tumor necrosis factor-like weak inducer of apoptosis, as a novel cytokine that mediates kidney inflammation in models of renal fibrosis. Inhibition of apoptosis via TWEAK inhibition has been shown to reduce kidney fibrosis. Recent studies using lineage tracing suggest that interstitial pericytes/perivascular fibroblasts differentiate into myofibroblasts and undergo proliferative expansion during fibrosis. Furthermore, increased expression of nuclear peroxisome proliferator-activated receptor-α in proximal tubules can directly reduce increased expression of transforming growth factor-β1 and interstitial inflammation in models of renal fibrosis, which suggests preservation of proximal tubule cell metabolism and integrity represents an important new therapeutic target. In this review, the current evidence and potential molecular mechanisms involved in the development of kidney fibrosis are discussed.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Virginia, Charlottesville, Va., USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Portilla
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D016922:Cellular Senescence; D002945:Cisplatin / Q000633:toxicity; D000074049:Cytokine TWEAK; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D058628:Myofibroblasts / Q000473:pathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020286:Pericytes / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D017582:Renal Replacement Therapy; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000074049:Cytokine TWEAK; D005227:Fatty Acids; D047493:PPAR alpha; D018124:Receptors, Tumor Necrosis Factor; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D000255:Adenosine Triphosphate; D002945:Cisplatin