SGLT2 Inhibition for Diabetic and Non-diabetic Kidney Disease

Chronic kidney disease (CKD) can be progressive, and its prognosis is worse because of increased mortality when it is associated with diabetes and cardiac disease. The outcomes of diabetic kidney disease (DKD) need to be improved, despite multifactorial interventions including glucose and blood pressure (BP) control, and the use of renin-angiotensin system (RAS) inhibitors, statins, and aspirin. Recent clinical trials suggest that sodium-glucose cotransporter-2 (SGLT2) inhibitors offer additional cardiorenal protection in DKD and non-diabetic CKD on top of RAS inhibition. The action of SGLT2 inhibitors is derived from the proximal tubule of the kidney, but their systemic effects beyond glucose-lowering involve hemodynamic and non-hemodynamic mechanisms. First, SGLT2 inhibitors restore tubuloglomerular feedback and relieve glomerular hypertension and albuminuria. Second, natriuresis and renal glycosuria lead to fluid and weight loss, resulting in BP lowering and prevention of heart failure. Third, SGLT2 inhibitors have anti-inflammatory and anti-oxidative actions that can reduce renal and cardiac inflammation and fibrosis, probably via adenosine monophosphate-activated protein kinase and sirtuin-1 activation. Finally, the proximal tubular workload is relieved, accompanied by increased erythropoiesis. Hypoxia-inducible factor 1 may be stimulated by renal outer medullary hypoxia when tubular sodium transport shifts from the proximal convoluted tubule to the proximal straight tubule and thick ascending limb, due to SGLT2 inhibition. These effects may also be beneficial in non-diabetic CKD, and we anticipate that SGLT2 inhibitors will prove effective for albuminuria reduction and preservation of kidney function in primary kidney diseases, including glomerulonephritis.

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Sex-specific Effects of SGLT2 Inhibition in a Kidney with Reduced Nephron Number: Modeling and Analysis

10.1101/2021.12.16.472644 ◽

2021 ◽

Author(s):

Anita Layton

Keyword(s):

Kidney Disease ◽

Kidney Function ◽

Diabetic Kidney Disease ◽

Sglt2 Inhibitors ◽

Male And Female ◽

Renal Effects ◽

Diabetic Kidney ◽

Sodium Glucose Cotransporter ◽

Patients With Diabetes ◽

Sglt2 Inhibition

The kidney plays an essential role in regulating the homeostasis of electrolytes, acid-base species, and fluids. Kidney structure and function are significantly affected in diabetes. These pathophysiological changes include glomerular hyperfiltration and tubular hypertrophy, and ultimately leading to diabetic kidney disease. A class of medications that have shown promise in slowing the progression to diabetic kidney disease are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors target Na+ and glucose reabsorption along the proximal convoluted tubule, enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes. We postulate that both diabetes-induced and SGLT2 inhibition-induced changes in kidney may exhibit significant sex differences, because the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules, and (iii) study how those renal effects are altered in uninephrectomy. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes and/or uninephredctomy. The simulation results indicate that by inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis.

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Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors

Nature Reviews Nephrology ◽

10.1038/s41581-021-00393-8 ◽

2021 ◽

Author(s):

Ralph A. DeFronzo ◽

W. Brian Reeves ◽

Alaa S. Awad

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Sglt2 Inhibitors ◽

Diabetic Kidney ◽

Disease Impact

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The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22041525 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1525

Author(s):

Chunling Huang ◽

Ji Bian ◽

Qinghua Cao ◽

Xin-Ming Chen ◽

Carol A. Pollock

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Kidney Diseases ◽

Mitochondrial Protein ◽

Physiological Role ◽

Close Link ◽

Promising Alternative ◽

Diabetic Kidney ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.

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SGLT2 Inhibitors and Other Novel Therapeutics in the Management of Diabetic Kidney Disease

Seminars in Nephrology ◽

10.1016/j.semnephrol.2021.03.003 ◽

2021 ◽

Vol 41 (2) ◽

pp. 85-95

Author(s):

Robert C. Stanton

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Sglt2 Inhibitors ◽

Diabetic Kidney ◽

Novel Therapeutics

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Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.729334 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dong-Yuan Chang ◽

Xiao-Qian Li ◽

Min Chen ◽

Ming-Hui Zhao

Keyword(s):

Kidney Disease ◽

Protective Effect ◽

High Glucose ◽

Diabetic Kidney Disease ◽

Membrane Attack Complex ◽

Sglt2 Inhibitors ◽

Tubulointerstitial Injury ◽

Diabetic Kidney ◽

Proximal Tubular Epithelial Cells ◽

Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

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Key profibrotic and pro-inflammatory pathways in the pathogenesis of diabetic kidney disease

Diabetic Nephropathy ◽

10.2478/dine-2021-0005 ◽

2021 ◽

Vol 1 (1) ◽

pp. 15-26

Author(s):

Devang M. Patel ◽

Yuxin Yang ◽

Kexin Shi ◽

Tieqiao Wu ◽

Mark E. Cooper ◽

...

Keyword(s):

Kidney Disease ◽

Renal Fibrosis ◽

Diabetic Kidney Disease ◽

Transforming Growth Factor ◽

Large Body ◽

Noncommunicable Disease ◽

Sirtuin 1 ◽

Type I ◽

Diabetic Kidney ◽

Inflammatory Pathways

Abstract Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.

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