High glucose instigates tubulointerstitial injury by stimulating hetero-dimerization of adiponectin and angiotensin II receptors

Zha, Dongqing; Cheng, Huaiyan; Li, Weiwei; Wu, Yizhe; Li, Xiaoning; Lian, Zhang; Yu, Feng; Wu, Xiaoyan

doi:10.1016/j.bbrc.2017.08.047

Cited by 21 publications

(25 citation statements)

References 33 publications

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“…Hyperglycemia directly destroys renal tubular cells, resulting in a wide range of cellular and metabolic dysfunctions. Three interrelated and cardinal pathways, including overproduction of reactive oxygen species (ROS), initiation of autophagy, and activation of the apoptotic pathway, are triggered by high glucose and are associated with the progression of DKD ( 32 , 33 ). Oxidative stress is a state of imbalance in the production of ROS and antioxidant activity in the body, resulting in the activation of downstream inflammation ( 34 ) and tubulointerstitial fibrosis-related genes such as transforming growth factor (TGF)- β 1 and RAAS-related genes ( 35 ).…”

Section: New Insights Into the Pathophysiology Of Renal Tubules In Dkdmentioning

confidence: 99%

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

et al. 2021

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Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.

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Section: New Insights Into the Pathophysiology Of Renal Tubules In Dkdmentioning

confidence: 99%

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

et al. 2021

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“…It is now widely accepted that AT 1 R is capable to form higher order complexes, i.e homodimers/oligomers and heterodimers/oligomers with other GPCRs. Several GPCR-AT 1 R heterodimers were published, including adiponectin receptor [76], α 2C -adrenergic receptor (α 2C AR ) [77], apelin receptor [78], β 2 AR [79], bradykinin B 2 receptor [80], CB 1 cannabinoid receptor [70], chemokine (C-C Motif) receptor 2 [81], prostaglandin F 2α receptor [82] and purinergic P2Y 6 receptor [83]. Interestingly, several dimers have been associated with altered ability to activate G protein and/or β-arrestins ( Fig.…”

Section: Dimer Formation Of At 1 R With Other Gpcrsmentioning

confidence: 99%

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Tóth

Turu

Hunyady

et al. 2018

Best Practice & Research Clinical Endocrinology & Metab

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AT angiotensin receptor (ATR), a prototypical G protein-coupled receptor (GPCR), is the main receptor, which mediates the effects of the renin-angiotensin system (RAS). ATR plays a crucial role in the regulation of blood pressure and salt-water homeostasis, and in the development of pathological conditions, such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Stimulation of ATR leads to pleiotropic signal transduction pathways generating arrays of complex cellular responses. Growing amount of evidence shows that ATR is a versatile GPCR, which has multiple unique faces with distinct conformations and signaling properties providing new opportunities for functionally selective pharmacological targeting of the receptor. Biased ligands of ATR have been developed to selectively activate the β-arrestin pathway, which may have therapeutic benefits compared to the conventional angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In this review, we provide a summary about the most recent findings and novel aspects of the ATR function, signaling, regulation, dimerization or oligomerization and its cross-talk with other receptors, including epidermal growth factor (EGF) receptor, adrenergic receptors and CB cannabinoid receptor. Better understanding of the mechanisms and structural aspects of ATR activation and cross-talk can lead to the development of novel type of drugs for the treatment of cardiovascular and other diseases.

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“…Although the underlying reason is not clear, it is possible that high blood glucose causes metabolic stress and directly triggers the damage to tubular epithelial cells, resulting in the excretion of mitochondrial fragments to the extracellular space and urine. Multiple studies showed that hyperglycemia affects renal tubular cells by several mechanisms: overproduction of reactive oxygen species (ROS), activation of apoptotic pathway, and initiation of autophagy [35–39]. Mitochondria, the powerhouse of all cells, are the center of these events.…”

Section: Discussionmentioning

confidence: 99%

Urinary mitochondrial DNA level as a biomarker of tissue injury in non-diabetic chronic kidney diseases

et al. 2018

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BackgroundUrinary mitochondrial DNA (mtDNA) fragment level has been proposed as a biomarker of chronic kidney disease (CKD). In this study, we determine the relation between urinary mtDNA level and rate of renal function deterioration in non-diabetic CKD.MethodsWe recruited 102 non-diabetic CKD patients (43 with kidney biopsy that showed non-specific nephrosclerosis). Urinary mtDNA level was measured and compared to baseline clinical and pathological parameters. The patients were followed 48.3 ± 31.8 months for renal events (need of dialysis or over 30% reduction in estimated glomerular filtration rate [eGFR]).ResultsThe median urinary mtDNA level was 1519.42 (inter-quartile range 511.81–3073.03) million copy/mmol creatinine. There were significant correlations between urinary mtDNA level and baseline eGFR (r = 0.429, p < 0.001), proteinuria (r = 0.368, p < 0.001), severity of glomerulosclerosis (r = − 0.537, p < 0.001), and tubulointerstitial fibrosis (r = − 0.374, p = 0.014). The overall rate of eGFR decline was − 2.18 ± 5.94 ml/min/1.73m2 per year. There was no significant correlation between the rate of eGFR decline and urinary mtDNA level. By univariate analysis, urinary mtDNA level predicts dialysis-free survival, but the result became insignificant after adjusting for clinical and histological confounding factors.ConclusionUrinary mtDNA levels have no significant association with the rate of renal function decline in non-diabetic CKD, although the levels correlate with baseline renal function, proteinuria, and the severity of histological damage. Urinary mtDNA level may be a surrogate marker of permanent renal damage in non-diabetic CKD.

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High glucose instigates tubulointerstitial injury by stimulating hetero-dimerization of adiponectin and angiotensin II receptors

Cited by 21 publications

References 33 publications

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Urinary mitochondrial DNA level as a biomarker of tissue injury in non-diabetic chronic kidney diseases

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