Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats

Corremans, Raphaëlle; Neven, Ellen; Maudsley, Stuart; Leysen, Hanne; Broe, Marc E. De; D’Haese, Patrick C.; Vervaet, Benjamin A.; Verhulst, Anja

doi:10.1016/j.kint.2022.01.037

Cited by 16 publications

(11 citation statements)

References 50 publications

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“…Besides that, the choice of the CKD model seems to matter. Tauber et al ( 48 ) using an adenine-induced CKD model and Vervaet and colleagues ( 49 ) using a CKD model with unilateral nephrectomy on high-salt diets detected no beneficial response to SGLT2 inhibition. In clinical practice, however, SGLT2 inhibitors seem to decrease chronic kidney disease progression independently of the underlying type of initial kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Chen

Delić

Cao

et al. 2023

American Journal of Physiology-Cell Physiology

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The mechanisms of nephroprotection in non-diabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham operated rats, placebo treated rats with 5/6 nephrectomy (5/6Nx); 5/6Nx + telmisartan (5mg/kg/day), 5/6Nx + empagliflozin (3mg/kg/day); 5/6Nx + empagliflozin (15mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of estimated glomerular filtration rate (eGFR). The urinary albumin to creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback mechanism (TGF). Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with interstitial kidney fibrosis and positively correlated with eGFR. Immunohistochemical analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T-cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a non-hypothesis driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1qa) as well as complement component 1Q subcomponent C chain (C1qc) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin mediated-nephroprotection in non-diabetic CKD is due to a dose dependent activation of the TGF as well as empagliflozin mediated effects on the complement system.

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Section: Discussionmentioning

confidence: 99%

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Chen

Delić

Cao

et al. 2023

American Journal of Physiology-Cell Physiology

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“…Moreover, in adenine-induced chronic kidney disease, treatment with canagliflozin (25 mg/kg/day) for four weeks failed to ameliorate the progressive loss of kidney function and there was no decreased interstitial area percentage, nor was there altered expression levels of genes related to fibrosis and inflammation. The authors concluded that canagliflozin dosage was not effective in a therapeutic setting of established non-diabetic CKD since canagliflozin treatment was started after four weeks of adenine treatment [37]. Canagliflozin (5 mg/kg/day) for one week was also shown to improve kidney function in isoprenaline-treated rats by stimulating antioxidant, anti-inflammatory, and anti-apoptotic signaling pathways [38].…”

Section: Canagliflozinmentioning

confidence: 99%

Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side

Abdelrahman,

Awad,

Abdel-Rahman

2024

JCM

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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently available for the management of type 2 diabetes mellitus. SGLT2i acts by inhibiting renal SGLT2, thereby increasing glucosuria and lowering serum glucose. Recent trials are emerging supporting a role for SGLT2i irrespective of the diabetic status pointing towards that SGLT2i have other mechanisms of actions beyond blood sugar control. In this review, we will shed light on the role of this group of medications that act as SGLT2i in non-diabetics focusing on pre-clinical and clinical data highlighting the mechanism of renoprotection and effects of SGLT2i in the non-diabetic kidneys.

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“…Conversely, unphosphorylated YAP/TAZ enter the nucleus to bind to TEAD1-4 or other transcription factors, thereby regulating proliferation and downregulating apoptosis-related gene expression ( Figure 3 ). Recent research suggests that the renal protective effects of metformin are also associated with the activation of the Hippo pathway ( Corremans et al, 2022 ). MST1 downregulation promotes renal dysfunction and fibrosis in db/db mice.…”

Section: Specific Cell Types and Associated Signaling Pathways For Dkdmentioning

confidence: 99%

Single-cell transcriptomics: A new tool for studying diabetic kidney disease

et al. 2023

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The kidney is a complex organ comprising various functional partitions and special cell types that play important roles in maintaining homeostasis in the body. Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and is an independent risk factor for cardiovascular diseases. Owing to the complexity and heterogeneity of kidney structure and function, the mechanism of DKD development has not been fully elucidated. Single-cell sequencing, including transcriptomics, epigenetics, metabolomics, and proteomics etc., is a powerful technology that enables the analysis of specific cell types and states, specifically expressed genes or pathways, cell differentiation trajectories, intercellular communication, and regulation or co-expression of genes in various diseases. Compared with other omics, RNA sequencing is a more developed technique with higher utilization of tissues or samples. This article reviewed the application of single-cell transcriptomics in the field of DKD and highlighted the key signaling pathways in specific tissues or cell types involved in the occurrence and development of DKD. The comprehensive understanding of single-cell transcriptomics through single-cell RNA-seq and single-nucleus RNA-seq will provide us new insights into the pathogenesis and treatment strategy of various diseases including DKD.

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Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats

Cited by 16 publications

References 50 publications

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side

Single-cell transcriptomics: A new tool for studying diabetic kidney disease

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