SGLT2 inhibition to target kidney aging

Abstract

Anti-aging therapy is the latest frontier in the world of medical science, especially for widespread diseases such as chronic kidney disease (CKD). Both renal aging and CKD are characterized by increased cellular senescence, inflammation and oxidative stress. A variety of cellular signalling mechanisms are involved in these processes, which provide new potential targets for therapeutic strategies aimed at counteracting the onset and progression of CKD. At the same time, sodium-glucose co-transporter 2 inhibitors (SGLT2is) continuously demonstrate large beneficial effects at all stages of the cardiorenal metabolic continuum. The broad-spectrum benefits of SGLT2is have led to changes in several treatment guidelines and to growing scientific interest in the underlying working principles. Multiple mechanisms have been studied to explain these great renal benefits, but many things remain to be solved. With this in mind, we provide an overview of the experimental evidence for the effects of SGLT2is on the molecular pathway's ability to modulate senescence, aging and parenchymal damage, especially at the kidney level. We propose to shed some light on the role of SGLT2is in kidney care by focusing on their potential to reduce the progression of kidney disease across the spectrum of aging and dysregulation of senescence.

Keywords: SGLT2 inhibitors; aging; chronic kidney disease; molecular pathways; senescence.

Figure 1:

Structural and functional changes in the kidney across the senescence–aging spectrum. AKI, glomerulonephritis and diabetic kidney disease lead to microscopic and macroscopic changes cutting across the senescence–aging spectrum. These changes imply kidney damage that is expressed in proteinuria and kidney function decline.

Figure 2:

Overview of various mechanisms involved in cellular senescence. The cell cycle becomes dysfunctional as telomere shortening and mitochondrial dysfunction cause DNA damage, the extracellular matrix is expanded and there is organelle injury and senescent cells develop a SASP that leads to chronic inflammation. All the kidney cells are involved—podocytes, tubules and endothelial cells.

Figure 3:

Molecular effects of SGLT2is on kidney aging. SGLT2is act on different metabolic pathways in order to protect kidney function and prevent damage: SIRT1 is able to deacetylate and activate NRF2 that regulates mitochondrial fitness; inhibition of mTOR mediates renoprotection; autophagy is affected by an elevated HIF-2α:HIF-1α ratio; and upregulation of AMPK, adiponectin and PPAR-α results in inhibition of chronic inflammation through energy deprivation. Furthermore, SGLT2is decrease oxidative stress in different ways: they inhibit NADPH-oxidase 4 and reduce the influx of glucose into RPTECs in order to increase ketone activation of the NRF2 pathway and mTOR inhibition; the decreased mitochondrial calcium overload contributes to upregulation of SIRT1 and SOD1 and 2. PPAR-α: peroxisome proliferator-activated receptor α.