Macrophages-Derived, LRG1-Enriched Extracellular Vesicles Exacerbate Aristolochic Acid Nephropathy Via A TGFβR1-Dependent Manner

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some herbal medicines, but treatment remains ineffective. We previously found NADPH oxidases 4 (NOX4), which regulates oxidative stress, play an important role in kidney injury model. However, its regulatory mechanism of action in AAN is still obscure. In this study, we established AAN model in vivo, a co-culture system of macrophage and TEC, and macrophage/TEC conditioned media culture model in vitro respectively. We found macrophages infiltration promoted injury，oxidative stress and apoptosis of TEC. Furthermore, the role of macrophage in AAN was dependent on macrophages-derived EV. Importantly, we found that macrophages-derived, Leucine-rich α-2-glycoprotein 1(LRG1)-enriched EV induced TEC injury and apoptosis of via a TGFβR1-dependent process. Mechanistically, macrophages-derived, LRG1-enriched EV mediating TECs injury by upregulating NOX4 in AAN model. This study may help design a better therapeutic strategy to treat AAN patients.

Aristolochic Acid Nephropathy as a Potential Model of Renal Senescence

The kidney is among the organs most susceptible to age-associated impairments. Although there has recently been extensive research on renal aging, appropriate models remain limited. Generally, renal aging is strongly associated with renal fibrosis, which is the final common pathway of chronic kidney disease. Aristolochic acid (AA), a nephrotoxic agent, causes aristolochic acid nephropathy (AAN), characterized by progressive renal fibrosis and functional decline. Here, we examined the potential of AAN as a model of renal senescence by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group presented aged kidney-like phenotypes such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidney, concomitant with increase in renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, followed by accumulation of reactive oxygen species. Additionally, Klotho, an antiaging gene, was significantly decreased in the kidney of AA-treated mice. Collectively, the results of the present study indicate that AAN partially mimics the aged kidney and may serve as a useful mouse model for research on renal aging.