Kidney fibrosis:from mechanisms to therapeutic medicines

Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessiveextracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD;However, at present noantifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation andfibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplaybetween 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 cellsinvolved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules areprofibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. Inaddition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigeneticchanges including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidneyfibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKDprogression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibroticinjury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers andantifibrotic treatment for CKD.

FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

Acute kidney injury(AKI)is a serious clinical complication with high morbidity and mortality rates.Despite substantial progress in understanding the mechanism of AKI,no effective therapy is available for treatment or prevention.We previously found that G protein-coupled receptor(GPCR)family member free fatty acid receptor 4(FFAR4)agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice.However,the versatile role of FFAR4 in kidney has not been well characterized.In the study,the expression of FFAR4 was abnormally decreased in tubular epithelial cells(TECs)of cisplatin,cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice,respectively.Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage,whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice.Notably,FFAR4,as a key determinant,was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs,which was indicated by senescence-associatedβ-galactosidase(SA-β-gal)activity,marker protein p53,p21,Lamin B1,phospho-histone H2A.X,phospho-Rb expression,and secretory phenotype IL-6 level.Mechanistically,pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein,where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs.These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

Analysis of biopsy-proven nephrotic syndrome in Tibetan patients

To the Editor:Nephrotic syndrome(NS)is a common clinical syndrome characterized by massive proteinuria and hypoalbuminemia,but it has never been investigated in the Tibetan population.This was a single-center,retrospective study of Tibetan patients who underwent renal biopsy from 2009 to 2016 in West China Hospital of Sichuan University.