Chronic kidney disease (CKD) is estimated to affect 10-14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplay between injured parenchyma (like tubular cells) and multiple non-parenchymal cell lineages (immune and mesenchymal cells) located spatially within scarring areas. Although the mechanisms of kidney fibrosis are complicated due to the kinds of cells involved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules are profibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. In addition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigenetic changes including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidney fibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKD progression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibrotic injury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers and antifibrotic treatment for CKD. 

https://www.nature.com/articles/s41392-023-01379-7.pdf

Kidney fibrosis: from mechanisms to therapeutic medicines

The fibrogenic niche in kidney fibrosis: components and mechanisms

Proteomic landscape of the extracellular matrix in the fibrotic kidney.

Kidney fibrosis is the final common pathway of virtually all chronic kidney diseases (CKDs) and is therefore considered to be a promising therapeutic target for these conditions. However, despite great progress in recent years, no targeted antifibrotic therapies for the kidney have been approved, likely because the complex mechanisms that initiate and drive fibrosis are not yet completely understood. Recent single-cell genomic approaches have allowed novel insights into kidney fibrosis mechanisms in mouse and human, particularly the heterogeneity and differentiation processes of myofibroblasts, the role of injured epithelial cells and immune cells, and their crosstalk mechanisms. In this review we summarize the key mechanisms that drive kidney fibrosis, including recent advances in understanding the mechanisms, as well as potential routes for developing novel targeted antifibrotic therapeutics. 

Mechanisms of kidney fibrosis and routes towards therapy

Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis. 

Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis

Endothelial cell injury leading to microvascular rarefaction is a characteristic feature of chronic kidney disease (CKD) However, the mechanism underlying endothelial cell dropout is poorly defined Here, we show a central role of the extracellular microenvironment in controlling endothelial cell survival and proliferation in CKD When cultured on a decellularized kidney tissue scaffold (KTS) from fibrotic kidney, endothelial cells increased the expression of proapoptotic proteins Proteomics profiling identified fibrillin-1 (FBN1) as a key component of the fibrotic KTS, which was up-regulated in animal models and patients with CKD FBN1 induced apoptosis of endothelial cells and inhibited their proliferation in vitro RNA sequencing uncovered activated integrin αvβ6/transforming growth factor–β signaling, and blocking this pathway abolished FBN1-triggered endothelial injury In a mouse model of CKD, depletion of FBN1 ameliorated renal fibrotic lesions and mitigated vascular rarefaction These studies illustrate that FBN1 plays a role in mediating vascular rarefaction by orchestrating a hostile microenvironment for endothelial cells

https://advances.sciencemag.org/content/advances/7/5/eabc7170.full.pdf

Fibrillin-1–enriched microenvironment drives endothelial injury and vascular rarefaction in chronic kidney disease

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Fibrillin-1–enriched microenvironment drives endothelial injury and vascular rarefaction in chronic kidney disease