Background/Purpose: Though immune targeted therapies have improved outcomes in lupus nephritis, a significant number of patients experience renal damage and even progression to end stage renal disease. Recently, sodium and glucose cotransporter 2 inhibitors (SGLT2i) have proven efficacious in preventing adverse renal outcomes in patients with a variety of chronic diseases. In addition to inducing shifts in cellular metabolism, SGLT2i have anti-inflammatory and antifibrotic properties. Here, we hypothesize that systemic SGLT2i-driven metabolic changes could modulate humoral autoimmunity and inflammation in lupus.

Methods: 10-week-old MRL/lpr female mice were treated daily with dapagliflozin at 10 mg/kg or vehicle by gavage for 11 weeks. NZB/NZWF1 female mice were treated daily with dapagliflozin (10mg/kg) by gavage at early (23 weeks) and late disease (28 weeks) for 10-12 weeks and monitored weekly for proteinuria (n = 10 mice/experimental group). Sera was collected to measure autoantibodies, creatinine, and glucose by ELISA and colorimetric assays. Immune cells were enumerated in the spleen, bone marrow (BM), and kidneys by flow cytometry, immunofluorescence, and ELISPOT. Inflammation, fibrosis, and immune cell infiltration were assessed in kidneys by histology and quantitative PCR. Metabolite abundances were analyzed with untargeted metabolomics on kidney tissue.

Results: SGLT2i therapy unexpectedly reduced autoreactive plasma cells (aPCs) in the spleen, BM, and kidney when initiated at early stages of disease in both mouse models (Figure 1 NZB/NZW). Splenic germinal centers (GCs) and generation of plasmablasts (PBs) in both spleen and BM were significantly inhibited in NZB/NZW mice treated early with dapagliflozin (p < 0.005 for splenic PBs, p ≤ 0.0001 for BM PBs, compared to vehicle treated). In contrast, though SGLT2i treatment of late disease was less efficacious to target splenic GCs, aPCs were still reduced (p < 0.05) in the kidney of NZB/NZW mice. T regulatory cells (Tregs) were systematically increased in the axillary lymph nodes, extrafollicular areas of the spleen, and renal interstitium of SGLT2i treated MRL/lpr mice (p < 0.005 compared to vehicle treated). We also observed a significant enrichment in regulatory T follicular helper cells in splenic GCs of SGLT2i-treated NZB/NZW mice (p ≤ 0.0001). Periarterial inflammation (p < 0.005, p < 0.05) and interstitial fibrosis (p < 0.005) were significantly ameliorated in the kidneys of MRL/lpr and NZB/NZW mice at early and late disease (Figure 2).

Conclusion: The immune modulatory and antifibrotic effects of SGLT2i in lupus prone mice support their potential as a novel treatment approach. Considering the essential role of glucose in the formation of GCs and plasma cells, our data suggests that a shift in glucose metabolism induced by SGLT2i may be the driving force behind the decrease in germinal centers, autoreactive plasma cells, and plasmablasts in MRL/lpr and NZB/NZW mice. Additional studies are underway to further define whether SGLT2i target oxidative stress in the kidney and to elucidate the systemic effects of SGLT2i on Tregs, GCs, and autoreactive PCs.

Figure 1. Dapagliflozin therapy at early stages of lupus impairs the production of splenic autoreactive antibody secreting cells (ASC) and affects their accumulation in the kidney and bone marrow (BM) of NZB/NZW female mice. 23 weeks old NZB/NZW female mice were treated with SGLT2i vs vehicle for 12 weeks. Spleen, kidney, and BM cell suspensions were used to enumerate dsDNA-specific IgG+ ASC by ELISpot. Live cells were counted by the trypan blue exclusion method to calculate the total number of autoreactive ASC per organ. A) Splenic, B) BM and C) renal dsDNA-specific IgG+ ASC were significantly reduced in NZB/NZW female mice treated with dapagliflozin. n = 8 – 10 NZB/NZW female mice/group. ND: No detected. Statistical significance was calculated with two-tailed, unpaired Student’s t test in data with normal distribution or with Mann Whitney in groups with no normal distribution. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.

Figure 2. Dapagliflozin therapy modulates interstitial kidney fibrosis at early and advanced lupus stages in NZB/NZW female mice. 23 weeks old (early lupus) or 28 weeks old NZB/NZW female mice (advanced lupus) were treated as previously described. Kidneys were fixed in neutral buffered formalin and embedded in paraffin. Kidney sections were stained with Masson’s Trichrome. Areas of interstitial fibrosis were measured with an automated tool of Zeiss microscope. A-C) Representative 200X magnification pictures of interstitial fibrosis in kidneys of NZB/NZW female mice treated with dapagliflozin at early stages of lupus. E-G) Representative 200X magnification pictures of interstitial fibrosis in kidneys of NZB/NZW female mice treated with dapagliflozin at advanced stages of lupus. Morphometric analysis of interstitial fibrosis after therapy at D) early lupus vs H) advanced lupus. Blue stain = collagen deposition. Scale bar = 20 µm. Statistical significance was calculated with two-tailed, unpaired Student’s t test in data with normal distribution or with Mann Whitney in groups with no normal distribution. **, p < 0.005; ****, p ≤ 0.0001.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sodium-glucose-co-transporter-2-inhibitors-modulate-renal-injury-and-autoreactive-plasma-cells-in-lupus/