Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

Yang, Yang; Xu, Gaosi

doi:10.3389/fendo.2022.872918

Cited by 22 publications

(21 citation statements)

References 134 publications

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“…In the context of T2DM, uncontrolled vascular tone can damage mesangial cells, further impairing renal filtration [ 92 ]. Renal proximal tubular arginase plays an important role in the kidney aging process [ 93 ] and also contributes to vascular dysfunction in apolipoprotein E deficient mice, leading to BBB leakage and neuroinflammation, which has been associated with endothelial dysfunction in T2DM [ 94 ].…”

Section: Discussionmentioning

confidence: 99%

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice

Zahid

Dafre

Currais

et al. 2023

IJMS

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db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer’s disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.

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Section: Discussionmentioning

confidence: 99%

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice

Zahid

Dafre

Currais

et al. 2023

IJMS

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“…In pathological conditions, such as diabetes or hypertension, the concentration of ET-1 is increased because of the hyperglycaemia, acidosis and the presence of insulin, angiotensin II and proinflammatory cytokines, which causes sustained vasoconstriction. This may contribute to deleterious effects such as hyperfiltration (mainly in early diabetic nephropathy or incipient obesity-related kidney disease [ 11 , 12 , 13 ]) or podocyte damage and, eventually, proteinuria and GFR decline ( Figure 1 ) [ 14 ].…”

Section: Introduction: the Endothelin Systemmentioning

confidence: 99%

Endothelin Receptor Antagonists in Kidney Disease

Martínez-Díaz

Martos

Llorens-Cebrià

et al. 2023

IJMS

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Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.

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“…Various mechanisms are involved in the pathogenesis of chronic kidney disease (CKD) including an inflammatory response, the activation of the renin–angiotensin–aldosterone system, and hyperfiltration [ 1 , 2 ]. Currently, blockades of the renin–angiotensin–aldosterone system have been used to attenuate the progression of CKD; however, they have failed to completely prevent disease progression.…”

Section: Introductionmentioning

confidence: 99%

The Role of V-Set Ig Domain-Containing 4 in Chronic Kidney Disease Models

Han

Ghee

Joo

et al. 2023

Life

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V-set Ig domain-containing 4 (VSIG4) regulates an inflammatory response and is involved in various diseases. However, the role of VSIG4 in kidney diseases is still unclear. Here, we investigated VSIG4 expression in unilateral ureteral obstruction (UUO), doxorubicin-induced kidney injury mouse, and doxorubicin-induced podocyte injury models. The levels of urinary VSIG4 protein significantly increased in the UUO mice compared with that in the control. The expression of VSIG4 mRNA and protein in the UUO mice was significantly upregulated compared with that in the control. In the doxorubicin-induced kidney injury model, the levels of urinary albumin and VSIG4 for 24 h were significantly higher than those in the control mice. Notably, a significant correlation was observed between urinary levels of VSIG4 and albumin (r = 0.912, p < 0.001). Intrarenal VSIG4 mRNA and protein expression were also significantly higher in the doxorubicin-induced mice than in the control. In cultured podocytes, VSIG4 mRNA and protein expressions were significantly higher in the doxorubicin-treated groups (1.0 and 3.0 μg/mL) than in the controls at 12 and 24 h. In conclusion, VSIG4 expression was upregulated in the UUO and doxorubicin-induced kidney injury models. VSIG4 may be involved in pathogenesis and disease progression in chronic kidney disease models.

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Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

Cited by 22 publications

References 134 publications

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice

Endothelin Receptor Antagonists in Kidney Disease

The Role of V-Set Ig Domain-Containing 4 in Chronic Kidney Disease Models

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