NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease

ABSTRACTBackgroundDiabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of all of the beneficial interventions implemented in patients with diabetes, there remains a need for additional therapeutic targets in diabetic kidney disease (DKD). Mitochondrial dysfunction and inflammation are increasingly recognized as important causes of the development and progression of DKD. However, the molecular connection between mitochondrial function, inflammation, and fibrosis remains to be elucidated.MethodsIn the present studies we tested the hypothesis that enhancing NAD metabolism could increase mitochondrial sirtuin 3 (SIRT3) activity, improve mitochondrial function, decrease mitochondrial DNA damage, and prevent inflammation and progression of DKD.ResultsWe found that treatment of db-db mice with type 2 diabetes with nicotinamide riboside (NR) prevented albuminuria, increased urinary KIM1 excretion, and several parameters of DKD. These effects were associated with increased SIRT3 activity, improved mitochondrial function, and decreased inflammation at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway.ConclusionsNR supplementation boosted the NAD metabolism to modulate mitochondrial function and inflammation and prevent progression of diabetic kidney disease.

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The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies

Medicina ◽

10.3390/medicina57090868 ◽

2021 ◽

Vol 57 (9) ◽

pp. 868

Author(s):

Michela Amatruda ◽

Guido Gembillo ◽

Alfio Edoardo Giuffrida ◽

Domenico Santoro ◽

Giovanni Conti

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Type 2 Diabetes ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

The United States ◽

Diabetic Kidney ◽

Onset Type ◽

Hereditary Component

Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.

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

Kidney360 ◽

10.34067/kid.0001252019 ◽

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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Albuminuria Is More Closely Associated with Vascular Endothelial Function than eGFR in Type 2 Diabetes with Diabetic Kidney Disease

Diabetes ◽

10.2337/db18-443-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 443-P

Author(s):

YOSHINORI KAKUTANI ◽

MASANORI EMOTO ◽

YUKO YAMAZAKI ◽

KOKA MOTOYAMA ◽

TOMOAKI MORIOKA ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Endothelial Function ◽

Diabetic Kidney Disease ◽

Vascular Endothelial ◽

Vascular Endothelial Function ◽

Diabetic Kidney

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539-P: The Trend of Diabetic Kidney Disease with Low eGFR and Absence of Albuminuria in Type 2 Diabetic Patients in Japan from 1996-2015

Diabetes ◽

10.2337/db19-539-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 539-P

Author(s):

YOSHINORI KAKUTANI ◽

MASANORI EMOTO ◽

KATSUHITO MORI ◽

YUKO YAMAZAKI ◽

AKINOBU OCHI ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Diabetic Kidney ◽

Type 2 Diabetic

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Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants ◽

10.3390/antiox10071143 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1143

Author(s):

Midori Sakashita ◽

Tetsuhiro Tanaka ◽

Reiko Inagi

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Stress Responses ◽

Diabetic Kidney Disease ◽

Renin Angiotensin System ◽

Therapeutic Agents ◽

Metabolic Changes ◽

Diabetic Kidney ◽

Glucose Levels ◽

Patients With Diabetes

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

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Dietary Phosphorus as a Marker of Mineral Metabolism and Progression of Diabetic Kidney Disease

Nutrients ◽

10.3390/nu13030789 ◽

2021 ◽

Vol 13 (3) ◽

pp. 789

Author(s):

Agata Winiarska ◽

Iwona Filipska ◽

Monika Knysak ◽

Tomasz Stompór

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Mineral Metabolism ◽

Careful Analysis ◽

Diabetic Kidney ◽

Dietary Phosphorus ◽

Patients With Diabetes ◽

Cv Disease ◽

End Stage ◽

Phosphorus Intake

Phosphorus is an essential nutrient that is critically important in the control of cell and tissue function and body homeostasis. Phosphorus excess may result in severe adverse medical consequences. The most apparent is an impact on cardiovascular (CV) disease, mainly through the ability of phosphate to change the phenotype of vascular smooth muscle cells and its contribution to pathologic vascular, valvular and other soft tissue calcification. Chronic kidney disease (CKD) is the most prevalent chronic disease manifesting with the persistent derangement of phosphate homeostasis. Diabetes and resulting diabetic kidney disease (DKD) remain the leading causes of CKD and end-stage kidney disease (ESRD) worldwide. Mineral and bone disorders of CKD (CKD-MBD), profound derangement of mineral metabolism, develop in the course of the disease and adversely impact on bone health and the CV system. In this review we aimed to discuss the data concerning CKD-MBD in patients with diabetes and to analyze the possible link between hyperphosphatemia, certain biomarkers of CKD-MBD and high dietary phosphate intake on prognosis in patients with diabetes and DKD. We also attempted to clarify if hyperphosphatemia and high phosphorus intake may impact the onset and progression of DKD. Careful analysis of the available literature brings us to the conclusion that, as for today, no clear recommendations based on the firm clinical data can be provided in terms of phosphorus intake aiming to prevent the incidence or progression of diabetic kidney disease.

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Diabetic kidney disease in patients with type 2 diabetes mellitus: a cross-sectional study

BMC Nephrology ◽

10.1186/s12882-021-02429-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Randa I. Farah ◽

Mohammed Q. Al-Sabbagh ◽

Munther S. Momani ◽

Asma Albtoosh ◽

Majd Arabiat ◽

...

Keyword(s):

Diabetes Mellitus ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Laboratory Data ◽

Cross Sectional Study ◽

Sectional Study ◽

Cross Sectional ◽

Diabetic Kidney ◽

Type 2 Dm

Abstract Aim Diabetic kidney disease (DKD) is a major long-term complication of diabetes mellitus (DM). Given the paucity of data on DKD in Jordan, we aimed to evaluate the prevalence, characteristics and correlates of DKD in Jordanian patients with type 2 DM. Methods This cross-sectional study included 1398 adult patients with type 2 DM who sought medical advice in the endocrinology clinic between March and September 2019. Demographic, clinical and laboratory data were reviewed. DKD was defined as reduced eGFR, and/or albuminuria. Three regression models were constructed to identify factors associated with CKD stages, albuminuria and DKD. Results Overall, 701 (50.14%) patients had DKD, with a median age of 59.71 ± 11.36 years. Older age, high triglycerides, and low high-density lipoprotein were associated with DKD (multivariable odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01–1.03, p < 0.01; OR: 1.1, 95% CI: 1.01–1.2; and OR: 0.98, 95% CI: 0.97–0.99, p < 0.01 respectively). Metformin and renin-angiotensin system blockers were negatively associated with albuminuria and chronic kidney disease stages (p < 0.01). Conclusion Our study demonstrated that approximately one half of patients with type 2 DM had DKD. Further studies are necessary to understand this high prevalence and the underlying factors. Future research are needed to assess implementing targeted community-based intervention.

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