NAD+ Homeostasis in Diabetic Kidney Disease

The redox reaction and energy metabolism status in mitochondria is involved in the pathogenesis of metabolic related disorder in kidney including diabetic kidney disease (DKD). Nicotinamide adenine dinucleotide (NAD+) is a cofactor for redox reactions and energy metabolism in mitochondria. NAD+ can be synthesized from four precursors through three pathways. The accumulation of NAD+ may ameliorate oxidative stress, inflammation and improve mitochondrial biosynthesis via supplementation of precursors and intermediates of NAD+ and activation of sirtuins activity. Conversely, the depletion of NAD+ via NAD+ consuming enzymes including Poly (ADP-ribose) polymerases (PARPs), cADPR synthases may contribute to oxidative stress, inflammation, impaired mitochondrial biosynthesis, which leads to the pathogenesis of DKD. Therefore, homeostasis of NAD+ may be a potential target for the prevention and treatment of kidney diseases including DKD. In this review, we focus on the regulation of the metabolic balance of NAD+ on the pathogenesis of kidney diseases, especially DKD, highlight benefits of the potential interventions targeting NAD+-boosting in the treatment of these diseases.

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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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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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N6 -(2-hydroxyethyl)-adenosine from Cordyceps cicadae protects against diabetic kidney disease via alleviation of oxidative stress and inflammation

Journal of Food Biochemistry ◽

10.1111/jfbc.12727 ◽

2018 ◽

Vol 43 (2) ◽

pp. e12727 ◽

Cited By ~ 6

Author(s):

Xiaohong Wang ◽

Aiqiong Qin ◽

Fang Xiao ◽

Opeyemi J. Olatunji ◽

Shuyuan Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Cordyceps Cicadae

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Sulodexide Protects Renal Tubular Epithelial Cells from Oxidative Stress-Induced Injury via Upregulating Klotho Expression at an Early Stage of Diabetic Kidney Disease

Journal of Diabetes Research ◽

10.1155/2017/4989847 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Yu Ning Liu ◽

Jingwei Zhou ◽

Tingting Li ◽

Jing Wu ◽

Shu Hua Xie ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Epithelial Cells ◽

Diabetic Kidney Disease ◽

Early Stage ◽

Collaborative Study ◽

Oxidative Activity ◽

Dependent Manner ◽

Diabetic Kidney ◽

Collaborative Study Group

The hypoalbuminuric effect of sulodexide (SDX) on diabetic kidney disease (DKD) was suggested by some clinical trials but was denied by the Collaborative Study Group. In this study, the diabetic rats were treated with SDX either from week 0 to 24 or from week 13 to 24. We found that 24-week treatment significantly decreased the urinary protein and HAVCR1 excretion, inhibited the interstitial expansion, and downregulated the renal cell apoptosis and interstitial fibrosis. Renoprotection was also associated with a reduction in renocortical/urinary oxidative activity and the normalization of renal klotho expression. However, all of these actions were not observed when SDX was administered only at the late stage of diabetic nephropathy (from week 13 to 24). In vitro, advanced glycation end products (AGEs) dose-dependently enhanced the oxidative activity but lowered the klotho expression in cultured proximal tubule epithelial cells (PTECs). Also, H2O2 could downregulate the expression of klotho in a dose-dependent manner. However, overexpression of klotho reduced the HAVCR1 production and the cellular apoptosis level induced by AGEs or H2O2. Our study suggests that SDX may prevent the progression of DKD at the early stage by upregulating renal klotho expression, which inhibits the tubulointerstitial injury induced by oxidative stress.

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Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease

Diabetes ◽

10.2337/db21-0316 ◽

2021 ◽

pp. db210316

Author(s):

Nehaben A. Gujarati ◽

Alexandra R. Leonardo ◽

Jessica M. Vasquez ◽

Yiqing Guo ◽

Bismark O. Frimpong ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Kidney

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Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

International Journal of Molecular Sciences ◽

10.3390/ijms221910822 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10822

Author(s):

Agata Winiarska ◽

Monika Knysak ◽

Katarzyna Nabrdalik ◽

Janusz Gumprecht ◽

Tomasz Stompór

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Kidney Injury ◽

Organ Protection ◽

In Vivo Models ◽

Diabetic Kidney ◽

And Oxidative Stress

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

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