Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Irrespective of the initial causes, renal fibrogenesis is a dynamic and converging process that consists of four overlapping phases: priming, activation, execution and progression. Nonresolving inflammation after a sustained injury sets up the fibrogenic stage (priming) and triggers the activation and expansion of matrix-producing cells from multiple sources through diverse mechanisms, including activation of interstitial fibroblasts and pericytes, phenotypic conversion of tubular epithelial and endothelial cells and recruitment of circulating fibrocytes. Upon activation, matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates input from various fibrogenic signals and orchestrates the production of matrix components and their extracellular assembly. Multiple cellular and molecular events, such as tubular atrophy, microvascular rarefaction and tissue hypoxia, promote scar formation and ensure a vicious progression to end-stage kidney failure. This Review outlines our current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into the development of new therapeutic strategies.

/pdf/cellular-and-molecular-mechanisms-of-renal-fibrosis-41xwzf10im.pdf

Cellular and molecular mechanisms of renal fibrosis

Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the 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 higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.

Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development

The discovery of the myofibroblast has opened new perspectives for the comprehension of the biological mechanisms involved in wound healing and fibrotic diseases. In recent years, many advances have been made in understanding important aspects of myofibroblast basic biological characteristics. This review summarizes such advances in several fields, such as the following: i) force production by the myofibroblast and mechanisms of connective tissue remodeling; ii) factors controlling the expression of α-smooth muscle actin, the most used marker of myofibroblastic phenotype and, more important, involved in force generation by the myofibroblast; and iii) factors affecting genesis of the myofibroblast and its differentiation from precursor cells, in particular epigenetic factors, such as DNA methylation, microRNAs, and histone modification. We also review the origin and the specific features of the myofibroblast in diverse fibrotic lesions, such as systemic sclerosis; kidney, liver, and lung fibrosis; and the stromal reaction to certain epithelial tumors. Finally, we summarize the emerging strategies for influencing myofibroblast behavior in vitro and in vivo, with the ultimate goal of an effective therapeutic approach for myofibroblast-dependent diseases.

Recent developments in myofibroblast biology: paradigms for connective tissue remodeling.

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 by using unbiased single-cell RNA sequencing. On the basis of gene expression patterns, we infer that inherited kidney diseases that arise from distinct genetic mutations but share the same phenotypic manifestation originate from the same differentiated cell type. We also found that the collecting duct in kidneys of adult mice generates a spectrum of cell types through 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.

/pdf/single-cell-transcriptomics-of-the-mouse-kidney-reveals-37xko1d9wy.pdf

Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease

Tubulointerstitial fibrosis is a chronic and progressive process affecting kidneys during aging and in chronic kidney disease (CKD), regardless of cause CKD and renal fibrosis affect half of adults above age 70 and 10% of the world's population Although no targeted therapy yet exists to slow renal fibrosis, a number of important recent advances have clarified the cellular and molecular mechanisms underlying the disease In this review, I highlight these advances with a focus on cells and pathways that may be amenable to therapeutic targeting I discuss pathologic changes regulating interstitial myofibroblast activation, including profibrotic and proinflammatory paracrine signals secreted by epithelial cells after either acute or chronic injury I conclude by highlighting novel therapeutic targets and approaches with particular promise for development of new treatments for patients with fibrotic kidney disease

Mechanisms of Renal Fibrosis.

Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.

/pdf/epithelial-notch-signaling-regulates-interstitial-fibrosis-rucr218vdj.pdf

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

Diabetic kidney disease (DKD) is one of the most devastating complications of diabetes. Renal dysfunction develops in about one-third of patients with diabetes (1). Diabetic nephropathy is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Current therapies for DKD, including blood glucose control, angiotensin II receptors blockers, and ACE inhibitors, slow down, but do not halt, the progression to end-stage renal disease after overt nephropathy has been established (2). Recent studies indicate that podocyte injury and depletion play key roles in the pathogenesis of DKD (3,4). Clinical observational studies showed a strong correlation between podocyte density, albuminuria and renal function decline in patients with type 1 and type 2 diabetes (5).

Notch signaling regulates many aspects of metazoan development and tissue renewal (6). Notch is a transmembrane protein that interacts with ligands of the Jagged and Delta family (7). In mammals, there are four Notch receptors (Notch 1–4), two Jaggeds, and three delta-like ligands (8). Each of these proteins show a cell type- and tissue-specific expression. Notch is made in the endoplasmic reticulum as pre-Notch. A furin-like convertase cleaves pre-Notch to intracellular and extracellular domain. The protein is then transported to the plasma membrane. Interaction of the ligand with the Notch receptor triggers a series of proteolytic cleavage, by ADAM, a disintegrin and metalloprotease and by the γ-secretase complex. The final cleavage releases the Notch intracellular domain (NICD), which then moves to the nucleus, where it can regulate gene …

https://diabetes.diabetesjournals.org/content/diabetes/59/8/1865.full.pdf

Getting a Notch Closer to Understanding Diabetic Kidney Disease

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Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

Getting a Notch Closer to Understanding Diabetic Kidney Disease