scholarly journals Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
James Shaffner ◽  
Bohan Chen ◽  
Deepak K. Malhotra ◽  
Lance D. Dworkin ◽  
Rujun Gong
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Therapeutic Potential ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Metabolic Reprogramming ◽  
Therapeutic Modality ◽  
Future Research ◽  
Bodyweight Loss ◽  
Diabetic Kidney

As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m2, associated with a constellation of signs of metabolic reprogramming, including enhanced ketogenesis, which may be responsible for the correction of metabolic reprogramming that underlies DKD. This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.

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

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.

scholarly journals MicroRNAs in Diabetic Kidney Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Rong Li ◽  
Arthur C. K. Chung ◽  
Xueqing Yu ◽  
Hui Y. Lan
Keyword(s):  
Kidney Disease ◽  
Messenger Rna ◽  
Diabetic Kidney Disease ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Diagnostic Tools ◽  
Diabetic Kidney ◽  
Functional Studies ◽  
Gene Expression Studies

Rapid growth of diabetes and diabetic kidney disease exerts a great burden on society. Owing to the lack of effective treatments for diabetic kidney disease, treatment relies on drugs that either reduces its progression or involve renal replacement therapies, such as dialysis and kidney transplantation. It is urgent to search for biomarkers for early diagnosis and effective therapy. The discovery of microRNAs had lead to a new era of post-transcriptional regulators of gene expression. Studies from cells, experimental animal models and patients under diabetic conditions demonstrate that expression patterns of microRNAs are altered during the progression of diabetic kidney disease. Functional studies indicate that the ability of microRNAs to bind 3′ untranslated region of messenger RNA not only shows their capability to regulate expression of target genes, but also their therapeutic potential to diabetic kidney disease. The presence of microRNAs in plasma, serum, and urine has been shown to be possible biomarkers in diabetic kidney disease. Therefore, identification of the pathogenic role of microRNAs possesses an important clinical impact in terms of prevention and treatment of progression in diabetic kidney disease because it allows us to design novel and specific therapies and diagnostic tools for diabetic kidney disease.

Diabetic Kidney Disease

2019 ◽  
pp. 277-286
Author(s):  
John Cijiang He
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Pressure Control ◽  
Sglt2 Inhibitors ◽  
New Drugs ◽  
Diabetic Kidney ◽  
Mesangial Area ◽  
The World ◽  
Effective Drugs

Diabetic kidney disease (DKD) is the most common cause of ESRD in USA as well as in the world. The incidence and the prevalence of DKD have been increasing regardless of current intervention. The pathology of DKD is characterized by accumulation of extracellular matrix in GBM and mesangial area. The pathogenesis of DKD is multi-factorial including genetic, metabolic, and hemodynamic changes, which lead to activation of oxidative stress, inflammation, and fibrosis pathways in the diabetic kidney. Clinically, patients with DKD presents with glomerular hyperfiltration at early stage, then microalbuminuria, macroalbuminuria, and ESRD. However, the disease progression varies greatly among individual patients. Treatment of DKD is limited to hyperglycemic and blood pressure control and use of RAS blockade. Several new drugs such as SGLT2 inhibitors have been on phase 3 clinical trials but research is required to develop more effective drugs to treat DKD.

scholarly journals Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Kidney360 ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. 292-299
Author(s):  
David J. Leehey
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Standard Of Care ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Low Grade ◽  
Diabetic Kidney ◽  
Raas Blockade ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

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