Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

Abstract

Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure, or glomerular filtration pressures. Their effects to promote erythrocytosis suggest that these drugs act on hypoxia-inducible factors (HIFs; specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α and thereby augment erythropoiesis, while muting organellar dysfunction, inflammation, and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney. Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure, or glomerular filtration pressures. Their effects to promote erythrocytosis suggest that these drugs act on hypoxia-inducible factors (HIFs; specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α and thereby augment erythropoiesis, while muting organellar dysfunction, inflammation, and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney. Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert striking effects to slow the deterioration of glomerular function in patients with type 2 diabetes. Additionally, in large-scale randomized placebo-controlled clinical trials, treatment with these drugs have reduced the risk for kidney failure by ~30%.1Neuen B.L. Young T. Heerspink H.J.L. et al.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2019; 7: 845-854Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar These benefits were seen within 2 to 3 years of treatment and were observed in diabetic patients with both preserved and impaired glomerular function at study entry.2Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (1993) Google Scholar The favorable effects of SGLT2 inhibitors on diabetic chronic kidney disease (CKD) cannot be explained by their action to lower blood glucose levels. The degree of renoprotection is not closely associated with the antihyperglycemic effect in individual patients,2Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (1993) Google Scholar and drugs that have greater glucose-lowering effects do not produce a rapid and marked reduction in adverse renal events. Similarly, the renal benefits of SGLT2 inhibitors cannot be ascribed to their modest action to lower blood pressure because even intensive control of blood pressure does not prevent serious renal events in type 2 diabetes.3Wang J. Chen Y. Xu W. Lu N. Cao J. Yu S. Effects of intensive blood pressure lowering on mortality and cardiovascular and renal outcomes in type 2 diabetic patients: a meta-analysis.PLoS One. 2019; 14e0215362Crossref PubMed Scopus (13) Google Scholar SGLT2 inhibitors alleviate the increased intraglomerular filtration pressure that has been implicated in the genesis of diabetic nephropathy. Their inhibitory effects in the proximal renal tubule promote sodium delivery to the macula densa, which (through tubuloglomerular feedback) mitigates the afferent arteriolar vasodilatation produced by hyperglycemia.4Cherney D.Z. Perkins B.A. Soleymanlou N. et al.Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.Circulation. 2014; 129: 587-597Crossref PubMed Scopus (826) Google Scholar However, such an action has been disputed,5van Bommel E.J.M. Muskiet M.H.A. van Baar M.J.B. et al.The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.Kidney Int. 2020; 97: 202-212Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar and the reduction in glomerular hyperfiltration produced by experimental knockout of SGLT2 does not prevent kidney injury.6Vallon V. Gerasimova M. Rose M.A. et al.SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice.Am J Physiol Renal Physiol. 2014; 306: F194-F204Crossref PubMed Scopus (311) Google Scholar Furthermore, SGLT2 inhibitors exert renal benefits in patients with glomerular filtration rates that are low enough to negate the ability of these drugs to cause glycosuria and decrease glomerular filtration pressures.2Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (1993) Google Scholar Furthermore, SGLT2 inhibitors exert favorable effects in patients in whom glomerular hyperfiltration has already been meaningfully ameliorated with the use of inhibitors of the renin-angiotensin system.2Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (1993) Google Scholar Collectively, these observations suggest that SGLT2 inhibitors exert renoprotective benefits by acting on nonhemodynamic pathogenic mechanisms within the kidney. In clinical trials in type 2 diabetes, the pharmacologic profile of SGLT2 inhibitors is distinguished by 2 physiologic effects that are not seen with other antihyperglycemic drugs: ketogenesis and erythrocytosis. It is unlikely that the ketogenic action of SGLT2 inhibitors is responsible for the ability of these drugs to reduce the risk for serious renal events. Circulating levels of ketone bodies are already increased in patients with diabetes and the diabetic kidney is a ketogenic organ, in the absence of SGLT2 inhibition.7Zhang D. Yang H. Kong X. et al.Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes.Am J Physiol Endocrinol Metab. 2011; 300: E287-E295Crossref PubMed Scopus (44) Google Scholar Furthermore, ketonemia dilates afferent arterioles, thereby promoting glomerular hyperfiltration and its injurious effects and thus ketogenesis is likely to exacerbate (rather than ameliorate) diabetic nephropathy.8Nosadini R. Trevisan R. Fioretto P. et al.Kidney hemodynamics after ketone body and amino acid infusion in normal and IDDM subjects.Diabetes. 1989; 38: 75-83Crossref PubMed Scopus (36) Google Scholar Additionally, SGLT2 inhibitors cause erythrocytosis by enhancing the production of erythropoietin,9Mazer C.D. Hare G.M.T. Connelly P.W. et al.Effect of empagliflozin on erythropoietin levels, iron stores and red blood cell morphology in patients with type 2 diabetes and coronary artery disease.Circulation. 2020; 141: 704-707Crossref PubMed Scopus (103) Google Scholar and some have proposed that an increase in oxygen-carrying capacity of the blood might improve kidney function. However, erythropoietin mimetics that yield increases in erythrocyte counts comparable to those seen with SGLT2 inhibitors do not favorably affect the course of kidney disease.10Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1572) Google Scholar Nevertheless, the parallel effect of SGLT2 inhibitors to promote the production of erythropoietin and ameliorate the decline in glomerular function suggests that these 2 effects may have a shared underlying mechanism. It is therefore noteworthy that hypoxia-inducible factors (HIFs) are the primary driver of erythropoietin synthesis,11Eckardt K.U. Kurtz A. Regulation of erythropoietin production.Eur J Clin Invest. 2005; 35: 13-19Crossref PubMed Scopus (94) Google Scholar and additionally, derangements in HIF signaling have been implicated in the pathogenesis of diabetic CKD.12Persson P. Palm F. Hypoxia-inducible factor activation in diabetic kidney disease.Curr Opin Nephrol Hypertens. 2017; 26: 345-350Crossref PubMed Scopus (29) Google Scholar Is it possible that an effect of SGLT2 inhibitors on HIFs contributes to the renoprotective actions of these drugs? HIFs regulate red blood cell synthesis by transactivating the gene for erythropoietin. Two inducible isoforms, HIF-1α and HIF-2α, are upregulated by hypoxia or by drugs that mimic hypoxia under normoxic conditions (eg, cobalt chloride).11Eckardt K.U. Kurtz A. Regulation of erythropoietin production.Eur J Clin Invest. 2005; 35: 13-19Crossref PubMed Scopus (94) Google Scholar,12Persson P. Palm F. Hypoxia-inducible factor activation in diabetic kidney disease.Curr Opin Nephrol Hypertens. 2017; 26: 345-350Crossref PubMed Scopus (29) Google Scholar These 2 isoforms coordinately regulate the of and that a in promoting oxygen delivery erythrocytosis and and oxygen use pathways and that HIF-2α is the that is responsible for erythropoietin K.U. Kurtz A. Regulation of erythropoietin production.Eur J Clin Invest. 2005; 35: 13-19Crossref PubMed Scopus (94) Google Scholar This action is related to the of HIF-2α in in the kidney, HIF-2α erythropoietin synthesis in the A. A. et are the renal that erythropoietin under hypoxia-inducible factor Int. Full Text Full Text PDF PubMed Scopus Google et erythropoietin in Clin Invest. PubMed Scopus Google Scholar In HIF-1α HIF-2α signaling is HIF-1α the of for and that decrease oxygen and it is in a of cell in the et to hypoxia by oxygen Metab. Full Text Full Text PDF PubMed Scopus Google Scholar HIF-1α and HIF-2α are by inhibition the actions of 1 or both HIF inhibition (eg, with erythropoietin synthesis and has been to the of in clinical N. X. et for in patients with kidney disease not Engl J Med. 2019; PubMed Scopus Google Scholar However, the erythrocytosis produced by these drugs is related to of the actions of HIF-2α, and not HIF-2α may in both the kidney and S. N. H. et a erythropoietin production in the 2019; PubMed Scopus Google Scholar Cobalt is a hypoxia that by it augment the of both HIF-1α and S. M. Y. et renal in an type 2 diabetes PubMed Scopus Google Scholar it promotes erythrocytosis by to and signaling S. N. H. et a erythropoietin production in the 2019; PubMed Scopus Google Y. D. Hypoxia-inducible factor to cobalt in PubMed Scopus Google Scholar The of erythropoietin and of inhibitors in suggest that HIF-2α is in these a that has been in the experimental et erythropoietin synthesis in chronic kidney disease is caused by in Med. PubMed Scopus (13) Google Scholar In of these it likely that other drugs that promote erythropoietin production and in under stress (eg, SGLT2 act to promote HIF-2α In to their actions on HIFs are important of and are of and that to decrease oxygen et to hypoxia by oxygen Metab. Full Text Full Text PDF PubMed Scopus Google Scholar HIF-1α the and oxidative of and promotes the of M.J. signaling of PubMed Scopus Google Scholar HIF-2α the of M.J. M. et promotes of by 2014; Full Text Full Text PDF PubMed Scopus Google Scholar and act to suppress the of the important an effect with the that HIFs to of and the organellar of oxygen thus HIF-1α and HIF-2α signaling has a effect to oxidative stress in glomerular and renal tubular P. by oxidative stress and HIF-1α levels in diabetic Diabetes 2017; PubMed Scopus Google T. R. et of hypoxia-inducible and oxidative stress in the Scopus Google Scholar The suppression of organellar by HIFs an important because the of that oxygen is for activation of et not oxidative 2005; Full Text Full Text PDF PubMed Scopus Google Scholar the effect of both HIF-1α and HIF-2α to promote other of cellular stress that are by of low oxygen (eg, endoplasmic reticulum thereby enhancing the cellular to hypoxia and the of T. R. et of hypoxia-inducible and oxidative stress in the Scopus Google A. M.A. et reduces endoplasmic reticulum stress and hypoxia inducible in the of PubMed Scopus Google Scholar Therefore, the actions of HIF-1α and HIF-2α to activate and may a in the cellular to both oxygen deprivation and oxidative HIF-1α and HIF-2α signaling has effects to the function of these 2 isoforms have effects on proinflammatory and profibrotic both in the kidney and other action of HIFs in of renal is to increase oxygen delivery by promoting an action that is by HIF-1α not by et not oxidative 2005; Full Text Full Text PDF PubMed Scopus Google Scholar However, effect of HIF-1α to enhance is by activation of proinflammatory cell signaling, and profibrotic X. X. J. treatment renal and of in experimental One. 2014; PubMed Scopus Google Scholar which act collectively to promote the of nephropathy. 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PubMed Scopus (13) Google Scholar The diabetic kidney is characterized by in HIF-1α and HIF-2α signaling, and the of the actions of these isoforms to an important in the pathogenesis of by the kidney is by the by renal tubular sodium In type 2 diabetes, proximal sodium is V. A. oxygen in the proximal effects of and SGLT2 J Physiol Renal Physiol. PubMed Scopus Google Scholar and the increase in oxygen use of the kidney to A. Y. P. Renal in the of chronic kidney Physiol. 2017; PubMed Scopus Google Scholar In experimental renal hypoxia is an in diabetes and it may of kidney or albuminuria and of M. P. et al.Kidney hypoxia, to increased oxygen of hyperglycemia and oxidative PubMed Scopus Google S. N. H. Palm F. kidney hypoxia albuminuria in type 1 diabetic mice.Am J Physiol Renal Physiol. 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M.J. et in diabetic kidney and PubMed Scopus Google Scholar and thus it cannot function to cellular oxidative stress has been implicated in the and of both and renal tubular as as the of proinflammatory thus to the pathogenesis of diabetic F. M. stress and diabetic PubMed Scopus Google Scholar oxygen are an important to HIF-1α to their action to oxygen by and F. J. P. P. oxygen cause decrease in renal oxygen PubMed Scopus Google Scholar Additionally, hyperglycemia and promote HIF-1α in both glomerular and renal tubular T. J. affect in renal Endocrinol. PubMed Scopus Google T. Y. et glucose in glomerular a Int. 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Full Text Full Text PDF PubMed Scopus Google M. et cell and PubMed Scopus Google Scholar It is therefore noteworthy that even in the of hypoxia, activation of both and HIF-1α in the kidney are et 1 cellular to hypoxia by hypoxia-inducible factor 38: Full Text Full Text PDF PubMed Scopus Google J. et activation the of by and PubMed Scopus Google Scholar However, in striking Chen R. et of hypoxia-inducible factor signaling by the 2009; PubMed Scopus Google Scholar Therefore, the signaling that is seen in the renal in type 2 diabetes be to activate HIF-1α and suppress HIF-2α. a of the of renal hypoxia, cellular stress, and impaired nutrient deprivation signaling, it is not that experimental and clinical diabetic is by HIF-2α increased HIF-1α et erythropoietin synthesis in chronic kidney disease is caused by in Med. PubMed Scopus (13) Google Scholar HIF-1α activation and HIF-2α suppression promote the and that are to diabetic kidney et renal in type 1 diabetic PubMed Scopus Google Scholar the suppression of HIF-1α and the hypoxia activation of HIF-2α the of diabetic S. M. Y. et renal in an type 2 diabetes PubMed Scopus Google R. Y. T. et is the of the SGLT2 inhibitor for diabetic 2019; PubMed Scopus Google Scholar and cause SGLT2 in the proximal renal H. H. et glucose increases sodium-glucose cotransporter 2 and reduces in renal glucose PubMed Scopus Google Scholar the SGLT2 activation in the diabetic J. Y. et al.SGLT2 is increased in diabetic SGLT2 inhibition renal inflammation, and the of in diabetic 2017; Full Text Full Text PDF PubMed Scopus Google Scholar of the actions of SGLT2 has been to oxidative stress, dysfunction, inflammation, and cellular of J. Y. et al.SGLT2 is increased in diabetic SGLT2 inhibition renal inflammation, and the of in diabetic 2017; Full Text Full Text PDF PubMed Scopus Google A. et to glucose in renal J Physiol Renal Physiol. 2019; PubMed Scopus Google S. T. M. S. cotransporter oxidative stress tubular cell PubMed Scopus Google Scholar These effects on cellular are by SGLT2 inhibitors in experimental of diabetic kidney A. T. Y. N. S. an inhibitor of sodium-glucose cotransporter 2 and effects on experimental diabetic by PubMed Scopus Google M. T. et renoprotective effects of on diabetic in PubMed Scopus Google Scholar The by renal hypoxia in the SGLT2 and kidney disease has not been In the diabetic kidney, sodium is in the proximal renal which is to increase oxygen and to hypoxia in the renal A. Y. P. Renal in the of chronic kidney Physiol. 2017; PubMed Scopus Google M. P. et al.Kidney hypoxia, to increased oxygen of hyperglycemia and oxidative PubMed Scopus Google S. N. H. Palm F. kidney hypoxia albuminuria in type 1 diabetic mice.Am J Physiol Renal Physiol. PubMed Scopus Google Scholar as a hypoxia SGLT2 M. Y. F. Hypoxia-inducible sodium glucose 1 and SGLT2 in renal tubular under 2014; Full Text Full Text PDF PubMed Scopus Google Scholar that oxygen in the kidney is not a of HIF signaling of renal tubular sodium SGLT2 is upregulated in type 2 SGLT2 inhibitors proximal tubular sodium and thereby reduce oxygen and alleviate renal V. SGLT2 inhibition in a kidney with reduced and analysis of and J Physiol Renal Physiol. PubMed Scopus Google Scholar a these drugs may reduce the for HIF-1α R. Y. T. et is the of the SGLT2 inhibitor for diabetic 2019; PubMed Scopus Google Scholar The HIF-1α suppression by SGLT2 inhibitors has been proposed to underlie the renoprotective benefits of these R. Y. 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A. et of hypoxia-inducible factors prevents diabetic 26: PubMed Scopus Google Scholar an effect that is by Therefore, the of HIF-1α and HIF-2α signaling, erythropoietin and renoprotection with cobalt is similar to that seen with SGLT2 and is by the that cobalt SGLT2 in renal M. Y. F. Hypoxia-inducible sodium glucose 1 and SGLT2 in renal tubular under 2014; Full Text Full Text PDF PubMed Scopus Google Scholar HIF-2α activation by both SGLT2 inhibitors and cobalt may to the ability of these drugs to improve glucose for hypoxia-inducible factor in glucose 2017; PubMed Scopus Google H. cobalt treatment hyperglycemia in PubMed Scopus Google Scholar are to cobalt and SGLT2 inhibitors is seen in the clinical that in patients with or at risk for diabetic nephropathy. that have been to have been to the of N. X. et for in patients with kidney disease not Engl J Med. 2019; PubMed Scopus Google Scholar and their actions to HIF signaling might the course of diabetic In 2 inhibition to ameliorate HIF-1α in experimental of the diabetic M. S. T. et inhibitor and associated kidney disease in type 2 diabetic 2020; PubMed Scopus Google S. T. T. et al.The hypoxia-inducible factor inhibitor in renal in the of diabetic kidney Int. 2020; 97: Full Text Full Text PDF PubMed Scopus Google Scholar However, the to inhibition may not be to and it is action is related to an effect to activate HIF-1α because HIF-1α by inhibitors has been to renal in the diabetic et renal in type 1 diabetic PubMed Scopus Google S. H. Chen et of promotes renal and in Med. 2017; PubMed Scopus Google Scholar these drugs enhance the of both HIF-1α and HIF-2α, and it is their effect on HIF-2α not that is responsible for their action to promote the synthesis of A. A. et are the renal that erythropoietin under hypoxia-inducible factor Int. Full Text Full Text PDF PubMed Scopus Google S. N. H. et a erythropoietin production in the 2019; PubMed Scopus Google Scholar The that inhibitors have renoprotective effects because of their actions to activate HIF-2α has not been to The diabetic kidney is characterized by increased activation of HIF-1α suppression of HIF-2α. These actions to the effects of renal hypoxia, oxidative and endoplasmic reticulum stress, and and may to glomerular and renal tubular dysfunction, renal and and the in erythropoietin production seen in diabetic SGLT2 inhibitors to reduce HIF-1α and promote HIF-2α signaling in the diabetic kidney, by their actions to alleviate renal hypoxia and cellular stress and enhance nutrient deprivation These effects may to the ability of these drugs to augment while muting organellar and proinflammatory and profibrotic thereby the progression of diabetic nephropathy. Cobalt chloride, a drug conventionally as a has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation

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