SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have pleiotropic properties beyond blood glucose-lowering effects and modify important nonglycemic pathways, leading to end-organ protection. SGLT2 inhibitors display renoprotective effects in diabetic kidney disease, which creates a rationale for testing the therapeutic potential of this drug class in nondiabetic chronic kidney disease. Here, we have shown that dapagliflozin provided glomerular protection in mice with protein-overload proteinuria induced by bovine serum albumin (BSA), to a similar extent as an ACE inhibitor used as standard therapy for comparison. Dapagliflozin limited proteinuria, glomerular lesions, and podocyte dysfunction and loss. We provide the observation that SGLT2 was expressed in podocytes and upregulated after BSA injections. Through in vitro studies with cultured podocytes loaded with albumin we have identified what we believe to be a novel mechanism of action for SGLT2 inhibitor that directly targets podocytes and relies on the maintenance of actin cytoskeleton architecture. Whether SGLT2 inhibitors represent a possible future therapeutic option for some patients with proteinuric glomerular disease who do not have as yet an effective treatment will require ad hoc clinical studies.

Histological Evidence of Diabetic Kidney Disease Precede Clinical Diagnosis

“…It is reasonable to think that, when proteinuria occurs, kidneys of diabetic patients may already manifest minor to severe glomerular injuries. The early identification of this underdiagnosed group of DKD is crucial to promptly provide a specific therapeutic regimen, such as inhibitors of the renin-angiotensin system or, more recently, agents preventing progression of kidney failure [3,[53][54][55]. We acknowledge that performing a kidney biopsy by default in all diabetic patients is logistically demanding; however, considering our findings, the aim may be performing a kidney biopsy at least in diabetic subject with CKD Class II.…”

Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

“…Stimulation of HIF‐2α (which transactivates the gene for erythropoietin) may explain why SGLT2 inhibitors cause erythrocytosis in clinical trials . The enhanced interplay of AMPK, SIRT1 and HIF‐2α may underlie the action of SGLT2 inhibitors to ameliorate oxidative and endoplasmic reticular stress, and thereby minimize glomerular and tubular injury and inflammation, and attenuate the development of nephropathy . An increase in AMPK and SIRT1 may also directly enhance tubuloglomerular feedback, thereby linking changes in the activity of these energy sensors to the action of SGLT2 inhibitors to ameliorate glomerular hyperfiltration.…”

Histological evidences of diabetic kidney disease precede clinical diagnosis

“…TEM results essential in the early stages of renal involvement in diabetic patient. Early identification of this underdiagnosed group of DKD is crucial to promptly provide a specific therapeutic regimen able to slow disease progression (3,46,47); the coming of new antidiabetic drugs enforces the needing (48). We acknowledge that a standardized kidney biopsy for all diabetic patients is logistically demanding, however, in consideration of our findings, the challenge may be performing kidney biopsy in diabetic subject at least with CKD Class II.…”