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Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by autoreactive B cells and dysregulation of many other types of immune cells including myeloid cells. Lupus nephritis (LN) is a common target organ manifestations of SLE. Tonicity-responsive enhancer-binding protein (TonEBP, also known as nuclear factor of activated T-cells 5 (NFAT5)), was initially identified as a central regulator of cellular responses to hypertonic stress and is a pleiotropic stress protein involved in a variety of immunometabolic diseases. To explore the role of TonEBP, we examined kidney biopsy samples from patients with LN. Kidney TonEBP expression was found to be elevated in these patients compared to control patients - in both kidney cells and infiltrating immune cells. Kidney TonEBP mRNA was elevated in LN and correlated with mRNAs encoding inflammatory cytokines and the degree of proteinuria. In a pristane-induced SLE model in mice, myeloid TonEBP deficiency blocked the development of SLE and LN. In macrophages, engagement of various toll-like receptors (TLRs) that respond to damage-associated molecular patterns induced TonEBP expression via stimulation of its promoter. Intracellular signaling downstream of the TLRs was dependent on TonEBP. Therefore, TonEBP can act as a transcriptional cofactor for NF-κB, and activated mTOR-IRF3/7 via protein-protein interactions. Additionally, TonEBP-deficient macrophages displayed elevated efferocytosis and animals with myeloid deficiency of TonEBP showed reduced Th1 and Th17 differentiation, consistent with macrophages defective in TLR signaling. Thus, our data show that myeloid TonEBP may be an attractive therapeutic target for SLE and LN., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19 + B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild-type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild-type littermates. Co-treatment of wild-type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild-type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25 + /DTR + , but not in Nep25 + /DTR - mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25 + /DTR + than in DTR - mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25 + /DTR + than Nep25 + /DTR - mice with more severe sclerosis in the tubule-connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)