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.

No abstract

Our understanding of kidney disease pathogenesis is limited by an incomplete molecular characterization of the cell types responsible for the organ’s multiple homeostatic functions. To help fill this knowledge gap, we characterized 57,979 cells from healthy mouse kidneys using unbiased single-cell RNA sequencing. Based on gene expression patterns, we infer that inherited kidney diseases that arise from distinct genetic mutations but have similar phenotypic manifestations share the same cell of origin. We also found that the kidney collecting duct in adult mice generates a spectrum of cell types via a newly identified transitional cell. Computational cell trajectory analysis and in vivo lineage tracing revealed that intercalated cells and principal cells undergo transitions mediated by the Notch signaling pathway. In mouse and human kidney disease, these transitions were shifted toward a principal cell fate and were associated with metabolic acidosis.

Knowledge of cell type composition in disease relevant tissues is an important step towards the identification of cellular targets of disease. We present MuSiC, a method that utilizes cell-type specific gene expression from single-cell RNA sequencing (RNA-seq) data to characterize cell type compositions from bulk RNA-seq data in complex tissues. By appropriate weighting of genes showing cross-subject and cross-cell consistency, MuSiC enables the transfer of cell type-specific gene expression information from one dataset to another. When applied to pancreatic islet and whole kidney expression data in human, mouse, and rats, MuSiC outperformed existing methods, especially for tissues with closely related cell types. MuSiC enables the characterization of cellular heterogeneity of complex tissues for understanding of disease mechanisms. As bulk tissue data are more easily accessible than single-cell RNA-seq, MuSiC allows the utilization of the vast amounts of disease relevant bulk tissue RNA-seq data for elucidating cell type contributions in disease.

The kidney is arguably the most important target of microvascular damage in diabetes. A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease and/or other co-morbidity, including hypertension and ageing-related nephron loss. The presence and severity of chronic kidney disease (CKD) identify individuals who are at increased risk of adverse health outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the renin-angiotensin-aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. Indeed, the major decline in the incidence of diabetic kidney disease (DKD) over the past 30 years and improved patient prognosis are largely attributable to improved diabetes care. However, there remains an unmet need for innovative treatment strategies to prevent, arrest, treat and reverse DKD. In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression. In addition, we discuss the current evidence for the prevention and management of DKD as well as the many controversies. Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. For an illustrated summary of this Primer, visit: http://go.nature.com/NKHDzg.

OBJECTIVEDiabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney biopsy samples.RESEARCH DESIGN AND METHODSAffymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. DKD samples were significant for their racial diversity and decreased glomerular filtration rate (~25–35 mL/min). Stringent statistical analysis, using the Benjamini-Hochberg corrected two-tailed t test, was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. Two different web-based algorithms were used to define differentially regulated pathways.RESULTSWe identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli, and 330 probesets were commonly differentially expressed in both compartments. Pathway analysis highlighted the regulation of Ras homolog gene family member A, Cdc42, integrin, integrin-linked kinase, and vascular endothelial growth factor signaling in DKD glomeruli. The tubulointerstitial compartment showed strong enrichment for inflammation-related pathways. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in a different set of DKD samples.CONCLUSIONSOur studies have cataloged gene-expression regulation and identified multiple novel genes and pathways that may play a role in the pathogenesis of DKD or could serve as biomarkers.

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.

Diabetic nephropathy is the most common cause of endstage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyperglycemia in Ins2Akita (Akita) mice with type 1 diabetes and Lepr db/db (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37% reduction) and db/db (27% reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular reactive oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapoptotic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apoptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic nephropathy in murine type 1 and type 2 diabetic models. Diabetes 55: [225][226][227][228][229][230][231][232][233] 2006