SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney

Kidney diseases are a major global public health problem that imposes a heavy burden on families and society. Determining how to delay the progression of renal function impairment has become a global focus.  A sodium-glucose co-transporter-2 (SGLT2) inhibitor can reduce plasma glucose levels in patients with type 2 diabetes by increasing the amount of urine that is excreted in the blood. The benefits of treating diabetes with a SGLT2 inhibitor include reducing intrarenal hypoxia and reversing the metabolic reprogramming of the kidney. These renoprotective effects can be extended beyond glycemia control. Canagliflozin was proven to have significantly reduced the risk of developing a fatal or chronic kidney disease-related death and lower the levels of inflammatory and fibrotic mediators in plasma. Inflammasomes are multi-protein complexes that are involved in the regulation of various cellular processes. One of the most prominent inflammasomes is the pyrin domain-3, which is known to contribute to various kidney diseases. Its central protein, NLRP3, is an adaptor protein that facilitates the activation of the LRR-, NOD-, and the LRR-. This protein also cleaves various pro-IL molecules.

To have a better understanding of the mechanism of action of SGLT2 inhibitors on the renal tissue, Qingqing Ke, Caifeng Shi, Yunhui Lv, Lulu Wang, Jing Luo, Lei Jiang, Professor Junwei Yang, Dr. Yang Zhou from Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University. The researchers hypothesized that the blocking of the activation of the inflammasome and the accumulation of tricarboxylic acid cycle (TCAcycle) metabolites by Dapagliflozin could prevent the development of fibrosis. The original research article is now published in the Journal FASEB.

The research team analyzed the anti-fibrotic and anti-inflammatory effects of dapagliflozin, a SGLT2 inhibitor, on renal alternations using the ischemia/reperfusion-induced fibrosis model in mice. the mice were subjected to decreased renal perfusion by clamping the renal blood vessels, leading to a situation similar to renal fibrosis. They were subjected to a treatment with Dapaglifozin for 1 to 5 weeks. The authors found that kidney injury and damage to the renal tissue were significantly lower in mice treated with Dapaglifozin. The differences in the amino-acid metabolism, and TCA cycle between the mice treated and untreated with dapagliflozin groups were observed. The β-hydroxybutyrate levels were not significantly changed in the treatment groups. The effects of dapagliflozin on the β-hydroxybutyrate levels were also confirmed by the absolute concentrations of the compounds in the tissue.

The concentrations of the metabolites of the drug dapagliflozin in the tissue of mice revealed that it counteracts the effects of the changes in the energy metabolism caused by the fibrosis kidney. These findings suggest that the drug may benefit the development of an orchestrated TCA cycle in the kidney. The effects of dapagliflozin were confirmed by western blot. They showed that dapagliflozin reduced the upregulation of the NLRP3 and ASC, as well as the formation of an ASC speck. It was also found that the administration of a cell-permeable, itaconate surrogate prevented the activation of a protein known as NLRP3. However, these effects were abolished by the interference of IRG1, which suggests that the drug prevents the activation of NLRP3 via the production of TCA cycle metabolite itaconate. The authors important findings suggest that the effects of dapagliflozin on the development of progressive chronic kidney disease can be attributed to its ability to suppress both inflammation and metabolism.

Moreover, the study revealed that dapagliflozin prevented the activation of the rapamycin target in the kidney, which was known to contribute to the development of kidney inflammation. It also relieved the effects of the SGLT2 inhibitor on the kidney benefits. The treatment with dapagliflozin significantly increased the levels of IRG1 and CiC. It also decreased the IDH2 and prevented the activation of the inflammasome.

The new study confirms the renal benefits of SGLT2 inhibitors in kidney disease patients. It also reveals that dapagliflozin can reverse the effects of chronic kidney inflammation and increase the energy metabolism of the kidney. It also prevented the activation of the inflammasome by alleviating the accumulation of TCA cycle metabolites. It suggests that the use of the SGLT2 inhibitor could be beneficial for the treatment of various kidney diseases. The potential therapeutic benefits of Dapagliflozin and other SGLT2 inhibitors through the accumulation and regulation of immunomodulatory compounds could prove very promising.