Totally tubular, dude: rethinking DKD pathogenesis in the wake of SGLT2i data

Yu, Sherry H.; Leventhal, Jeremy S.; Cravedi, Paolo

doi:10.1007/s40620-020-00868-0

Cited by 6 publications

(5 citation statements)

References 9 publications

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“…Therefore, inhibiting SGLT2 can enhance the oxygenation of proximal tubules. Recent findings suggest that SGLT2i enhances ketolysis and autophagy while inhibiting mTORC1 expression ( 51 ). Proximal tubules are the main target of putative SGLT2i effects, but a study reported an upregulation of podocyte SGLT2 expression in a murine model of protein-overloaded proteinuria induced by bovine serum albumin (BSA), and treatment with SGLT2i dapagliflozin significantly improved albuminuria via restoration of cytoskeletal remodeling in the podocytes ( 52 ).…”

Section: Autophagic Cell Deathmentioning

confidence: 99%

Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease

Shen

Kai-feng

2022

Front. Endocrinol.

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Cellular senescence is frequently evident at etiologic sites of chronic diseases and involves essentially irreversible arrest of cell proliferation, increased protein production, resistance to apoptosis, and altered metabolic activity. Regulated cell death plays a vital role in shaping fully functional organs during the developmental process, coordinating adaptive or non-adaptive responses, and coping with long-term harmful intracellular or extracellular homeostasis disturbances. In recent years, the concept of ‘diabetic tubulopathy’ has emerged. tubular epithelial cells are particularly susceptible to the derangements of diabetic state because of the virtue of the high energy requirements and reliance on aerobic metabolism render. Hyperglycemia, oxidative stress, persistent chronic inflammation, glucose toxicity, advanced glycation end-products (AGEs) accumulation, lipid metabolism disorders, and lipotoxicity contribute to the cellular senescence and different patterns of regulated cell death (apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis) in tubular epithelial cells. We now explore the ‘tubulocentric’ view of diabetic kidney disease(DKD). And we summarize recent discoveries regarding the development and regulatory mechanisms of cellular senescence, apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis in the pathogenesis of DKD. These findings provide new perspectives on the mechanisms of DKD and are useful for designing novel therapeutic approaches for the treatment of DKD.

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Section: Autophagic Cell Deathmentioning

confidence: 99%

Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease

Shen

Kai-feng

2022

Front. Endocrinol.

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“…Among other effects, diminishing intraglomerular pressure and hyperfiltration, suppression of inflammation and fibrogenic pathways, protection against ischemic kidney damage, elevation of glucagon-like peptide-1 and glucagon levels, have been widely discussed[ 13 - 15 ]. Improving tubular metabolism and oxy-genation is considered another mechanism of the protective effect[ 16 ]. In glomeruli, podocytes may be the cornerstone of the effect of these drugs.…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

Климонтов¹,

Korbut²,

Taskaeva³

et al. 2020

WJD

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BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease. However, the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood. AIM To estimate the effect of the SGLT2 inhibitor, empagliflozin (EMPA), on the structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice. METHODS We treated 8-wk-old male db/db mice with EMPA (10 mg/kg/d) or vehicle for 8 wk. Age-matched male db/+ mice were included as non-diabetic controls. Parameters of body composition, glycemic and lipid control, and plasma concentrations of leptin, insulin and glucagon were assessed. We evaluated renal hypertrophy as kidney weight adjusted to lean mass, renal function as plasma levels of creatinine, and albuminuria as the urinary albumin-to-creatinine ratio (UACR). Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure, respectively. Glomerular nephrin and transforming growth factor beta (TGF-β) were assessed by immunohistochemistry. RESULTS Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment; increased plasma concentrations of fructosamine, glycated albumin, cholesterol, leptin, and insulin, and elevated UACR were detected. Mesangial expansion, glomerular basement membrane thickening, and increased area of TGF-β staining in glomeruli were revealed in vehicle-treated mice. Podocytopathy was manifested by effacement of foot processes; nephrin-positive areas in glomeruli were reduced. EMPA decreased the levels of glucose, fructosamine and glycated albumin, UACR, kidney hypertrophy, mesangial expansion, glomerular basement membrane thickening, and glomerular TGF-β staining, alleviated podocytopathy and restored glomerular staining of nephrin. CONCLUSION These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease. The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.

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“…This evidence indicates that podocyte dysfunction, instead of podocyte loss, might be a prime driver of impaired permselectivity in the glomerulus. Although DKD pathogenesis theories focused on podocyte dysfunction for a long time, the underlying mechanism contributing to the initial injury of podocytes has not been fully identified 57 . A recent study used ovalbumin (OVA) as a model antigen together with transgenic OT‐I T cells bearing a T‐cell receptor specific for OVA 257–264 (SIINFEKL) 58 .…”

Section: Pathogenic Role Of T Cells In the Development Of Dkdmentioning

confidence: 99%

Role of the adaptive immune system in diabetic kidney disease

Kong

Andrikopoulos

MacIsaac

et al. 2021

J of Diabetes Invest

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Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end‐stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro‐inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon‐γ and tumor necrosis factor‐α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

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Totally tubular, dude: rethinking DKD pathogenesis in the wake of SGLT2i data

Cited by 6 publications

References 9 publications

Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease

Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease

Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

Role of the adaptive immune system in diabetic kidney disease

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