Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors

Abstract

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation—sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)—can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter–2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Nephroprotection by SGLT2 Inhibition: Back to the Future?

“…Furthermore, besides the antihyperglycemic effect and associated reduction in glucotoxicity, SGLT2i may improve endothelial function via several mechanisms including weight loss and decreased body fat due to daily energy losses of up to 300 kcal (related to glycosuria 70–80 g/day), decreased insulin resistance and reduced uric acid levels [ 26 , 27 , 28 , 29 ]. More recent data suggest a role for the reduction in oxidative and endoplasmic reticulum stress due to the increment in autophagic flux in podocytes and renal tubules [ 30 ]. Of relevance are the anti-fibrotic or anti-inflammatory effects of SGLT2i.…”

Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders

“…SIRT1 activation leads to downregulation of HIF-1α ( 36 ) but upregulation of HIF-2α ( 37 ); the latter effect is likely mediated by SIRT1-mediated deacetylation of HIF-2α. In many chronic disorders (e.g., obesity, diabetes, chronic heart failure, and chronic kidney disease), the activity of SIRT1 is suppressed ( 38 , 39 ), thus shifting the balance toward upregulation of HIF-1α and downregulation of HIF-2α. Conversely, activation of SIRT1 activation favors HIF-2α over HIF-1α, and SIRT1 has direct effects to preserve the integrity of mitochondria and peroxisomes similar to the actions of HIF-2α ( 40 ).…”

“…The interplay between HIF-1α and HIF-2α may be particularly important in diabetes ( 78 ), because hyperglycemia and advanced glycation end products directly promote the transcription of HIF-1α in glomerular and renal tubular cells ( 83 , 84 ). In addition, SIRT1 signaling (along with its ability to inhibit HIF-1α and activate HIF-2α) is impaired in the diabetic kidney ( 38 , 39 ).…”

Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19

“…Despite a potential higher risk for SGLT2 inhibitors adverse effects in the context of acute illness and the resulting current advise against using them in COVID-19 patients, as recently emphasized [ 112 ], they have a favorable efficacy profile in preserving renal function, decreasing the impact of heart failure and increasing the survival of patients with risk factors for severe COVID-19. In preclinical studies, SGLT2 inhibitors had lung protective effects by decreasing oxidative stress, tissue hypoxia and inflammation [ 81 , 113 , 114 , 115 ]. Such an uncertainty regarding the use and risk-benefit balance of commonly prescribed drugs is not new in the history of treatment for severe disease or in the COVID-19 context.…”