Panax notoginseng saponins reverse steroid resistance in lupus nephritis: Involvement of the suppression of exosomal P-gp levels from lymphocytes to glomerular endothelial cells

Microangiopathy is the most basic pathological manifestation of lupus nephritis (LN), and glomerular endothelial cells (GECs) injury is an important pathological mechanism. LN patients with microangiopathy are prone to steroid resistance (SR). Our previous studies confirmed that Panax notoginseng saponins (PNS) could reverse SR by downregulating the expression of P-gp in SR lymphocytes of LN mice (SLCsL/S). However, the mechanism of how circulating lymphocytes transmit SR information to GECs and thus affect the efficacy of kidney treatment is not clear. Recent studies have found that exosomes (exos) are an important carrier for intercellular bioactive substance communication. But whether exosomes derived from SLCsL/S mediate SR in GECs and PNS interventions. To solve this problem, Exosomes isolated from SLCsL/S were characterized, and in vitro cell coculture was further conducted to investigate the effect of SLCsL/S-derived exosomes in the SR of GECs and PNS intervention. Sequencing was used to define the exosomal miRNA expression profiling of SR GECs. Moreover, the in vivo experiments were performed through the injection of exosomes extracted from SLCsL/S into the tail vein of mice.Our research results indicate that exosomes derived from SLCsL/S could transmit SR information to GECs and lead to the aggravation of inflammatory injury through conferring P-gp, which were negated by a P-gp inhibitor. Further, we identified higher levels of exosomal miR-125b-5p from SR GECs were associated with SR in LN and could serve as biomarker for the risk of developing SR. PNS could reverse the SR of GECs and alleviate inflammatory injury by suppressing exosomal P-gp levels from lymphocytes to GECs in vitro and in vivo. However, the specific molecular mechanism by which PNS regulates exosomes has not yet been elucidated, and we need to conduct more in-depth research in the future. Overall, Our findings suggest that exosomal transfer of SLCsL/S derived P-gp confer SR to GECs, and PNS can target exosome communication to reverse SR in LN, which provides new ideas and a scientific basis for improving the clinical efficacy of traditional Chinese medicine in the treatment of refractory LN.