scholarly journals The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

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.

A common glomerular transcriptomic signature distinguishes diabetic kidney disease from other kidney diseases in humans and mice

2020 ◽  
Vol 68 (4) ◽  
pp. 225-236
Author(s):  
Moustafa Abdalla ◽  
Mohamed Abdalla ◽  
Ferhan S. Siddiqi ◽  
Laurette Geldenhuys ◽  
Sri N. Batchu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Diabetic Kidney ◽  
Transcriptomic Signature

scholarly journals The Loss of Mitochondrial Quality Control in Diabetic Kidney Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenni Dai ◽  
Hengcheng Lu ◽  
Yinyin Chen ◽  
Danyi Yang ◽  
Lin Sun ◽  
...  
Keyword(s):  
Quality Control ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Protein Quality ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Eukaryotic Cell ◽  
Mitochondrial Quality Control ◽  
Diabetic Kidney

Diabetic kidney disease (DKD) is the predominant complication of diabetes mellitus (DM) and the leading cause of chronic kidney disease and end-stage renal disease worldwide, which are major risk factors for death. The pathogenesis of DKD is very complicated, including inflammation, autophagy impairment, oxidative stress, and so on. Recently, accumulating evidence suggests that the loss of mitochondrial quality control exerts critical roles in the progression of DKD. Mitochondria are essential for eukaryotic cell viability but are extremely vulnerable to damage. The mechanisms of mitochondrial quality control act at the molecular level and the organelle level, including mitochondrial dynamics (fusion and fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control. In this review, we summarize current knowledge of the role of disturbances in mitochondrial quality control in the pathogenesis of DKD and provide potential insights to explore how to delay the onset and development of DKD.

scholarly journals Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

2021 ◽  
Author(s):  
Hua Qu ◽  
Xiaoli Gong ◽  
Xiufei Liu ◽  
Rui Zhang ◽  
Yuren Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Glycerol 3 Phosphate Dehydrogenase

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, <a>contributing</a> to the global burden of kidney failure, cardiovascular morbidity and death. The key cell <a>type</a> that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we <a>characterized</a> the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated <a>diabetes-</a> or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury <a>significantly improved</a> their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

scholarly journals Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

2021 ◽  
Author(s):  
Hua Qu ◽  
Xiaoli Gong ◽  
Xiufei Liu ◽  
Rui Zhang ◽  
Yuren Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Glycerol 3 Phosphate Dehydrogenase

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, <a>contributing</a> to the global burden of kidney failure, cardiovascular morbidity and death. The key cell <a>type</a> that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we <a>characterized</a> the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated <a>diabetes-</a> or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury <a>significantly improved</a> their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

scholarly journals High FIB4 index is an independent risk factor of diabetic kidney disease in type 2 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haruka Saito ◽  
Hayato Tanabe ◽  
Akihiro Kudo ◽  
Noritaka Machii ◽  
Moritake Higa ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Diabetic Patients ◽  
Prognostic Impact ◽  
Diabetic Kidney ◽  
Cox Regression Analysis ◽  
Type 2 Diabetic

AbstractNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) may be linked to development of chronic kidney diseases (CKD). The FIB4 index, a noninvasive liver fibrosis score, has been reported to predict CKD in non-diabetic patients, but there are no reports yet in diabetic cases. Therefore, we evaluated the prognostic impact of FIB4 index on the risk of developing diabetic kidney disease (DKD) in Japanese patients with type 2 diabetes in a retrospective cohort study. We assessed patients with type 2 diabetes with an eGFR ≥ 60 mL/min/1.73 m2 and without dipstick positive proteinuria (≥ 1 +) at their first visit to our department. Participants were divided into two groups based on the FIB4 index at their first visit: FIB4 index > 1.3 and FIB4 index ≤ 1.3. The primary endpoint was defined as a decrease in eGFR < 60 mL/min/1.73 m2 or the onset of proteinuria during the course of treatment. The average age of all 584 type 2 diabetic participants (360 [61.6%] men) was 55 ± 11 years. There were 187 patients in the FIB4 index group > 1.3 (32.0%) and the median observation period was 6.0 (3.8–11.0) years. Kaplan–Meier survival analysis indicated that the risks of developing DKD, eGFR < 60 and proteinuria were all higher in FIB4 index > 1.3 patients than in FIB4 ≤ 1.3 patients. In the Cox regression analysis, an FIB4 index > 1.3 was a significant predictor for onset of DKD (HR 1.54, 95% CI 1.15–2.08) and proteinuria (HR 1.55, 95% CI 1.08–2.23), but not for an eGFR < 60 (HR 1.14, 95% CI 0.79–1.99). To the best of our knowledge, this is the first study to demonstrate that an FIB4 index > 1.3 has a prognostic impact on the development of CKD and proteinuria in type 2 diabetic patients. This warrants further investigation of the prognostic impact of the development of DKD or proteinuria.

scholarly journals NAD+ Homeostasis in Diabetic Kidney Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Jing Xu ◽  
Munehiro Kitada ◽  
Daisuke Koya
Keyword(s):  
Oxidative Stress ◽  
Energy Metabolism ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
Redox Reactions ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Related Disorder ◽  
Diabetic Kidney ◽  
Mitochondrial Biosynthesis

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.

scholarly journals RAS and sex differences in diabetic nephropathy

2016 ◽  
Vol 310 (10) ◽  
pp. F945-F957 ◽  
Author(s):  
Sergi Clotet ◽  
Marta Riera ◽  
Julio Pascual ◽  
María José Soler
Keyword(s):  
Sex Differences ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Sex Hormones ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Critical Role ◽  
Experimental Studies ◽  
Renin Angiotensin System ◽  
Diabetic Kidney

The incidence and progression of kidney diseases are influenced by sex. The renin-angiotensin system (RAS) is an important regulator of cardiovascular and renal function. Sex differences in the renal response to RAS blockade have been demonstrated. Circulating and renal RAS has been shown to be altered in type 1 and type 2 diabetes; this enzymatic cascade plays a critical role in the development of diabetic nephropathy (DN). Angiotensin-converting enzyme (ACE) and ACE2 are differentially regulated depending on its localization within the diabetic kidney. Furthermore, clinical and experimental studies have shown that circulating levels of sex hormones are clearly modulated in the context of diabetes, suggesting that sex-dependent RAS regulation may also be affected in these individuals. The effect of sex hormones on circulating and renal RAS may be involved in the sex differences observed in DN progression. In this paper we will review the influence of sex hormones on RAS expression and its relation to diabetic kidney disease. A better understanding of the sex dimorphism on RAS might provide a new approach for diabetic kidney disease treatment.

scholarly journals Complement, a Therapeutic Target in Diabetic Kidney Disease

2021 ◽  
Vol 7 ◽  
Author(s):  
Kelly Budge ◽  
Sergio Dellepiane ◽  
Samuel Mon-Wei Yu ◽  
Paolo Cravedi
Keyword(s):  
Innate Immunity ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Clinical Success ◽  
Systemic Diseases ◽  
Novel Therapy ◽  
Diabetic Kidney ◽  
Potential Benefits ◽  
The Complement System

Currently available treatments of diabetic kidney disease (DKD) remain limited despite improved understanding of DKD pathophysiology. The complement system is a central part of innate immunity, but its dysregulated activation is detrimental and results in systemic diseases with overt inflammation. Growing evidence suggests complement activation in DKD. With existent drugs and clinical success of treating other kidney diseases, complement inhibition has emerged as a potential novel therapy to halt the progression of DKD. This article will review DKD, the complement system's role in diabetic and non-diabetic disease, and the potential benefits of complement targeting therapies especially for DKD patients.

scholarly journals Epidermal Growth Factor Receptor: A Potential Therapeutic Target for Diabetic Kidney Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Lili Sheng ◽  
George Bayliss ◽  
Shougang Zhuang
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Kidney Disease ◽  
Epidermal Growth Factor ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Growth Factor Receptor ◽  
Acute Injury ◽  
Diabetic Kidney ◽  
Epidermal Growth

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide and the major cause of renal failure among patients on hemodialysis. Numerous studies have demonstrated that transient activation of epidermal growth factor receptor (EGFR) pathway is required for promoting kidney recovery from acute injury whereas its persistent activation is involved in the progression of various chronic kidney diseases including DKD. EGFR-mediated pathogenesis of DKD is involved in hemodynamic alteration, metabolic disturbance, inflammatory response and parenchymal cellular dysfunction. Therapeutic intervention of this receptor has been available in the oncology setting. Targeting EGFR might also hold a therapeutic potential for DKD. Here we review the functional role of EGFR in the development of DKD, mechanisms involved and the perspective about use of EGFR inhibitors as a treatment for DKD.

scholarly journals Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy

2019 ◽  
Vol 7 (1) ◽  
pp. e000720 ◽  
Author(s):  
Xiaohui Bian ◽  
Tomás P Griffin ◽  
Xiangyang Zhu ◽  
Md Nahidul Islam ◽  
Sabena M Conley ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Human Kidney ◽  
Activin A ◽  
Diabetic Kidney ◽  
Mesenchymal Transition

ObjectiveActivin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD.Research design and methodsIn two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin.ResultsPlasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (rs=−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (rs=0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased.ConclusionsCirculating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

Sign in / Sign up

Export Citation Format

Share Document