Editorial: Podocytes as Active Participants in Lupus Nephritis

Rifkin, Ian R.; Bonegio, Ramon

doi:10.1002/art.40157

Cited by 4 publications

(5 citation statements)

References 37 publications

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“…It has been widely recognised that the activation of the NLRP3 inflammasome induces podocyte injury and promotes proteinuria in patients with LN 26–29. SGLT2 inhibitors were reported to be capable of modulating NLRP3 inflammasome activity in diabetes,30 cardiovascular disease31 and kidney diseases 15 32.…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy

Zhao¹,

Li²,

He³

et al. 2023

Ann Rheum Dis

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ObjectivesThe protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown.MethodsWe applied empagliflozin treatment to lupus-prone MRL/lprmice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms.ResultsIn MRL/lprmice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lprmice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors.ConclusionThis study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.

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Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy

Zhao¹,

Li²,

He³

et al. 2023

Ann Rheum Dis

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“…APOL1 alleles G1 and G2, found in ~12% of African Americans, are risk factors for developing a spectrum of nondiabetic kidney diseases 3–5 , including LN and LN-ESRD 6,7 . Damage of kidney glomerular podocytes observed in LN 8–10 suggests that increased expression of APOL1 risk variants in podocytes of SLE patients may contribute to faster progression to LN and LN-ESRD. Because of an incomplete penetrance of the APOL1 risk alleles, environmental factors have been proposed as the key triggers of APOL1 expression and kidney damage in African Americans 18 .…”

Section: Discussionmentioning

confidence: 99%

“…Injury of kidney glomerular podocytes 8–10 is one of the hallmarks of LN that develops in ~40–70% of patients with systemic lupus erythematosus (SLE) 11 . Both in vitro 12–16 and in vivo 17 overexpression of APOL1 in podocytes is highly toxic.…”

Section: Introductionmentioning

confidence: 99%

Nucleosomal dsDNA Stimulates APOL1 Expression in Human Cultured Podocytes by Activating the cGAS/IFI16-STING Signaling Pathway

Davis

Khatua

Popik

2019

Sci Rep

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APOL1 alleles G1 and G2 are associated with faster progression to lupus nephritis (LN)-associated end-stage renal disease (LN-ESRD) in African Americans. Increased levels of type I interferons (IFNs) and nucleosome-associated double-stranded DNA (dsDNA) fragments (nsDNA) are the hallmark of this disease. Here, we identify cyclic GMP-AMP synthase (cGAS) and interferon-inducible protein 16 (IFI16) as the major DNA sensors in human immortalized podocytes. We also show that nsDNA triggers the expression of APOL1 and IFNβ via IRF3 activation through the cGAS/IFI16-STING pathway. We demonstrate that maximal APOL1 expression also requires the activation of type I IFN receptor (IFNAR) and STAT1 signaling triggered by IFNβ produced in response to nsDNA, or by exogenous IFNβ. Finally, we show that STAT1 activation is sufficient to upregulate IFI16, subsequently boosting APOL1 expression through a positive feedback mechanism. Collectively, we find that nsDNA-induced APOL1 expression is mediated by both IFNβ-independent and dependent signaling pathways triggered by activation of the cGAS/IFI16-STING pathway. We propose that simultaneous inhibition of STING and the IFNAR-STAT1 pathway may attenuate IFI16 expression, reduce IFI16-cGAS cross-talk, and prevent excessive APOL1 expression in human podocytes in response to nsDNA.

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“…Impair to podocyte structure is one of the early symptoms of glomerular injury and is a characteristic of LN (155)(156)(157). Podocytes are highly differentiated epithelial cells that are fixed on the basement membrane through the extension of the foot process and interact with the surrounding podocytes to form a slit diaphragm and eventually a filtration barrier.…”

Section: Ifn-i Promotes Glomerular Sclerosis Podocytementioning

confidence: 99%

“…The APOL1 allele G1 and G2 are risk factors for LN and end-stage renal disease associated with lupus nephritis (LN-ESRD) in African Americans (164,165). The observed injury of glomerular podocytes in LN suggests that the increase of APOL1 risk variant in podocytes of SLE patients may promote the faster progression of LN and LN-ESRD (155)(156)(157). Recent studies have shown that IFN-a is also associated with damage to podocyte structure and function.…”

Section: Ifn-i Promotes Glomerular Sclerosis Podocytementioning

confidence: 99%

IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

Ding

Ren

2021

Front. Immunol.

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Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

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Editorial: Podocytes as Active Participants in Lupus Nephritis

Cited by 4 publications

References 37 publications

SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy

SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy

Nucleosomal dsDNA Stimulates APOL1 Expression in Human Cultured Podocytes by Activating the cGAS/IFI16-STING Signaling Pathway

IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

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