Fibrosis is the histological manifestation of a progressive usually irreversible process causing chronic and end stage kidney disease. Genome-wide transcriptome studies of a large cohort (n=95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses identified inflammation and metabolism as top dysregulated pathways in diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and increased intracellular lipid deposition. In vitro experiments indicated that inhibition of fatty acid oxidation in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition; a phenotype observed in fibrosis. Restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect may be useful for preventing and treating chronic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. DKD is a prototypical disease of gene and environmental interactions. Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. Blood pressure control, especially with medications that inhibit the angiotensin system, is the only effective way to slow disease progression. While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. Concerted clinical and basic research efforts will be needed to understand DKD pathogenesis and to identify novel drug targets.

BackgroundOne in eleven people is affected by chronic kidney disease, a condition characterized by kidney fibrosis and progressive loss of kidney function. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a long-lasting role in chronic kidney disease development. Epigenetic information represents a plausible carrier for mediating this programming effect. Here we demonstrate that genome-wide cytosine methylation patterns of healthy and chronic kidney disease tubule samples obtained from patients show significant differences.ResultsWe identify differentially methylated regions and validate these in a large replication dataset. The differentially methylated regions are rarely observed on promoters, but mostly overlap with putative enhancer regions, and they are enriched in consensus binding sequences for important renal transcription factors. This indicates their importance in gene expression regulation. A core set of genes that are known to be related to kidney fibrosis, including genes encoding collagens, show cytosine methylation changes correlating with downstream transcript levels.ConclusionsOur report raises the possibility that epigenetic dysregulation plays a role in chronic kidney disease development via influencing core pro-fibrotic pathways and can aid the development of novel biomarkers and future therapeutics.

The kidney has a tremendous capacity to regenerate following injury, but factors that govern this response are still largely unknown. We isolated cells from mouse kidneys with high proliferative and multi-lineage differentiation capacity. These cells expressed high level of Sox9. In regenerating kidneys, Sox9 expression was induced early and 89% of proliferating cells were Sox9 positive. In vitro, Sox9 positive cells showed unlimited proliferation and multi-lineage differentiation capacity. Using an inducible Sox9 cre line and lineage tagging methods, we show that Sox9 positive cells can supply new daughter cells, contributing to the regeneration of proximal tubule, loop of Henle and distal tubule segments, but not to collecting duct and glomerular cells. Furthermore, inducible deletion of Sox9 resulted in reduced epithelial proliferation, more severe injury and fibrosis development. In summary, we demonstrate that in the kidney, Sox9 positive cells show progenitor-like properties in vitro, and contribute to epithelial regeneration following injury in vivo.

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