Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that SGLT2 protein was expressed in human and mouse podocytes to a similar extent of tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wildtype podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with the decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.

Response to: Correspondence on ‘SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy’ by Zhao et al

“…Soler, Cacha and Anders also showed concerns regarding the expression of SGLT2 in podocytes. The expression of SGLT2 can also be detected in the podocytes of Alport mice and mice with protein overload-induced proteinuria by immunofluorescence staining 6 7. We also observed SGLT2 expression in the proximal tubules, as demonstrated in the Results section.…”

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

“…Recently, renoprotective effects (with a special focus on podocyte) of SGLT2 inhibitors have been revealed in proteinuric non-diabetic nephropathy, membranous nephropathy and Alport syndrome 15 39 40. Despite the local renoprotective effects on renal resident cells like podocytes, our data suggested that SGLT2 inhibitors might have systemic immunological regulation effect contributing to renal protection.…”

SGLT2 Inhibitors are Blockbusters in Adults - But Not Studied in Children with Kidney Disease due to Industry Conflicts of Commercial Interest: A Call for Help To Regulators

“…14,15 In vivo, empagliflozin monotherapy reduces albuminuria and prolongs the kidney survival of AS mice, however, unlike what has been observed in patients enrolled in DAPA-CKD or EMPA Kidney, the addition of empagliflozin to the standard of care (SOC) ramipril did not confer additional renoprotection, and overall, no difference across treatment groups was observed. 12 In another set of experiments, Ramipril monotherapy prolonged mean lifespan of Alport mice to 77.3±5.3 days with no additional benefit for dual ACE/SGLT2 inhibition, which prolonged mean lifespan to 80.3±11.0 days. 13 Of note, the Alport mouse model is fast progressive, so treatment effects in human patients with Alport syndrome should be better than in animal models.…”

“…(1) Insufficient pre-clinical evidence for efficacy and safety to translate data from old adults to children Two recent high quality pre-clinical studies, 12,13 raise concerns that in children with glomerular diseases SGLT2-inhibitors may not be -as solid and as foolproof -effective as in EMPA Kidney and DAPA-CKD patients who are 5 to 7 times their average age. 14,15 In vivo, empagliflozin monotherapy reduces albuminuria and prolongs the kidney survival of AS mice, however, unlike what has been observed in patients enrolled in DAPA-CKD or EMPA Kidney, the addition of empagliflozin to the standard of care (SOC) ramipril did not confer additional renoprotection, and overall, no difference across treatment groups was observed.…”

“…If it comes to use of ACE-inhibitor in children with chronic kidney disease, we do not want to make a profit with a drug, but use it safely and effectively with the help of a Benefit-risk assessment by the European Medicines Agency EMA and the Food and Drug Administration FDA, which is absolutely possible due to the wide range of data for ACE-inhibitors in Alport syndrome. 2,[4][5][6][7]12,13,19 Now that ACE-inhibitors are and will remain standard of care anyway, why do we need advice by regulatory authorities? An assessment by the European Medicines Agency EMA and the Food and Drug Administration FDA would be extremely helpful, because the regulatory authorities have global expertise and an overall view of the data situation that is outstanding worldwide.…”