Effect of Combined Mycophenolate and Rapamycin Treatment on Kidney Fibrosis in Murine Lupus Nephritis.

Background: A significant proportion of lupus nephritis patients develop chronic kidney disease (CKD) and progressive kidney fibrosis, for which there is no specific treatment. We previously reported that mycophenolate or rapamycin monotherapy showed comparable efficacy in suppressing kidney fibrosis in a murine model of lupus nephritis through their direct action on mesangial cells. We extended our study to investigate the effect of combined mycophenolate and rapamycin treatment (MR) on kidney fibrosis in NZBWF1/J mice. Methods: Female NZBWF1/J mice with active nephritis were randomized to receive vehicle or treatment with mycophenolate (50 mg/kg/day) and rapamycin (1.5 mg/kg/day) (MR) for up to 12 weeks, and the effect of treatment on clinical parameters, kidney histology, and fibrotic processes was investigated. Results: Progression of nephritis in untreated mice was accompanied by mesangial proliferation, glomerulosclerosis, tubular atrophy, protein cast formation, increased mTOR and ERK phosphorylation, and induction of TGF-ß1, IL-6, α-smooth muscle actin, fibronectin, and collagen expression. Combined MR treatment prolonged survival, improved kidney function, decreased anti-dsDNA antibody level, and ameliorated histopathological changes. The effect of combined MR treatment on kidney histology and function was comparable to that of mycophenolate or rapamycin monotherapy. In vitro studies in human mesangial cells showed that exogenous TGF-ß1 and IL-6 both induced mTOR and ERK phosphorylation and downstream fibrotic processes. Both mycophenolic acid and rapamycin inhibited inflammatory and fibrotic processes induced by TGF-ß1 or IL-6 by downregulating mTOR and ERK phosphorylation. Conclusions: Our findings indicate that combined mycophenolate and rapamycin, at reduced dose, improves kidney fibrosis in murine lupus nephritis through their distinct effect on mTOR and ERK signaling in mesangial cells.

TGF-ß1 Signaling: Immune Dynamics of Chronic Kidney Diseases.

Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide, imposing a great burden on the healthcare system. Regrettably, effective CKD therapeutic strategies are yet available due to their elusive pathogenic mechanisms. CKD is featured by progressive inflammation and fibrosis associated with immune cell dysfunction, leading to the formation of an inflammatory microenvironment, which ultimately exacerbating renal fibrosis. Transforming growth factor ß1 (TGF-ß1) is an indispensable immunoregulator promoting CKD progression by controlling the activation, proliferation, and apoptosis of immunocytes via both canonical and non-canonical pathways. More importantly, recent studies have uncovered a new mechanism of TGF-ß1 for de novo generation of myofibroblast via macrophage-myofibroblast transition (MMT). This review will update the versatile roles of TGF-ß signaling in the dynamics of renal immunity, a better understanding may facilitate the discovery of novel therapeutic strategies against CKD.

Long Non-coding RNA LRNA9884 Promotes Acute Kidney Injury via Regulating NF-kB-Mediated Transcriptional Activation of MIF.

Acute kidney injury (AKI) is one of the most common complications affecting hospitalized patients associated with an extremely high mortality rate. However, the underlying pathogenesis of AKI remains unclear that largely limits its effective management in clinic. Increasing evidence demonstrated the importance of long non-coding RNAs (lncRNAs) in the pathogenesis of AKI, because of their regulatory roles in transcription, translation, chromatin modification, and cellular organization. Here, we reported a new role of LRNA9884 in AKI. Using experimental cisplatin-induced AKI model, we found that LRNA9884 was markedly up-regulated in the nucleus of renal tubular epithelium in mice with AKI. We found that silencing of LRNA9884 effectively inhibited the production of inflammatory cytokines MCP-1, IL-6, and TNF-α in the mouse renal tubular epithelial cells (mTECs) under IL-1ß stimulation in vitro. Mechanistically, LRNA9884 was involved into NF-κB-mediated inflammatory cytokines production especially on macrophage migration inhibitory factor (MIF). Collectedly, our study suggested LRNA9884 promoted MIF-triggered the production of inflammatory cytokines via NF-κB pathway after AKI injury. This study uncovered LRNA9884 has an adverse impact in AKI, and targeting LRNA9884 might represent a potential therapeutic target for AKI.