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

Abstract

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.

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

“…In a pilot randomized clinical trial, five LN patients who received additional treatment with empagliflozin showed a significant reduction in proteinuria. These encouraging results warrant validation in more extensive randomized clinical trials 74 …”

“…Orchestrated mechanisms involve reactive oxygen species production in hypoxia and mammalian target of rapamycin (mTORC1) inhibition in energy/nutrient deprivation 53,54 . CD36 overexpression promotes podocyte injury through nucleotide‐binding oligomerization domain‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation, 72,73 while inhibition of sodium‐glucose cotransporter (SGLT)2 alleviates podocyte injury via diminishing NLRP3 inflammasome and mTORC1 activation 74 . Opposite strand of homeobox A11 (HOXA11‐OS), a long noncoding RNA, regulates autophagy in podocytes through miR‐124‐3p/cysteine‐rich 61 sponging in LN.…”

“…These encouraging results warrant validation in more extensive randomized clinical trials. 74 A genetic variant of Apolipoprotein L1 (APOL1) is associated with autophagy in LN. Two drugs are available to inhibit APOL1 toxicity.…”

Emerging role of antidiabetic drugs in cardiorenal protection

“…Canagliflozin has been shown to inhibit CD4 + T cell activation and reduce cancer myelocytomatosis oncogene (cMyc) to prevent metabolic reprogramming and immune inflammation ( Jenkins et al, 2023 ). Consistently, a study by Zhao et al revealed that empagliflozin can inhibit the over-activated SGLT2 in lupus kidney glomeruli, prevent the activation of mechanistic target of rapamycin complex 1 (mTORC1), and delay glomerular injury in lupus kidney ( Zhao et al, 2023 ). Also, the expression of complement receptor type 1-related protein y (Crry), a key complement regulator, was upregulated by dapagliflozin, inhibiting HIF-1α accumulation under high glucose to alleviate immune inflammatory injury in db/db mice ( Chang et al, 2021 ).…”

SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback

“…24 SGLT2 inhibition may also alleviate podocyte injury and loss by dampening inflammation and activating autophagy through the inhibition of mTORC1 signaling. 75 SGLT2 inhibition may favorably influence the role of macrophages in kidney injury and repair. During acute injury, chemokines and complement components released by damaged cells promote monocyte recruitment and monocyte's differentiation into proinflammatory M1 macrophages.…”