Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease

Wang, Hua; Zhang, Shu; Guo, Jia

doi:10.3389/fmed.2021.751529

Cited by 16 publications

(11 citation statements)

References 94 publications

(144 reference statements)

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“…Lipid remodeling in the PT_S3 as identified in this study might provide an explanation to the role of this segment in the progression of kidney disease. Aberrant lipid metabolism has been recognized as primary event and progression factor in diabetic kidney disease 22 , 23 . PI lipid species give rise to polyphosphoinositides which are important signaling molecules involved in, among others, cell proliferation, vesicle trafficking and apoptosis 24 .…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes

Rietjens

Wang

Velden

et al. 2023

Sci Rep

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Diabetes is a main risk factor for kidney disease, causing diabetic nephropathy in close to half of all patients with diabetes. Metabolism has recently been identified to be decisive in cell fate decisions and repair. Here we used mass spectrometry imaging (MSI) to identify tissue specific metabolic dysregulation, in order to better understand early diabetes-induced metabolic changes of renal cell types. In our experimental diabetes mouse model, early glomerular glycocalyx barrier loss and systemic metabolic changes were observed. In addition, MSI targeted at small molecule metabolites and glycero(phospho)lipids exposed distinct changes upon diabetes in downstream nephron segments. Interestingly, the outer stripe of the outer medullar proximal tubular segment (PT_S3) demonstrated the most distinct response compared to other segments. Furthermore, phosphatidylinositol lipid metabolism was altered specifically in PT_S3, with one of the phosphatidylinositol fatty acid tails being exchanged from longer unsaturated fatty acids to shorter, more saturated fatty acids. In acute kidney injury, the PT_S3 segment and its metabolism are already recognized as important factors in kidney repair processes. The current study exposes early diabetes-induced changes in membrane lipid composition in this PT_S3 segment as a hitherto unrecognized culprit in the early renal response to diabetes.

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Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes

Rietjens

Wang

Velden

et al. 2023

Sci Rep

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“…This has been mainly described in tubules, and is frequently referred to as lipotoxicity in humans and rodents, as well as in vitro. (34,(40)(41)(42)(43)(44)(45)(46)(47) Furthermore, phosphorylation of GSK3β, as seen in the organoids, is known to be involved in high-glucose mediated lipid depositions in renal tubular cells. (47) A recent study of this kidney organoid model showed that, with the absence of CPT1, the proximal tubules fail to use the mitochondrial long-chain fatty acid metabolism (48), confirming our findings.…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural comparison of human kidney organoids and human fetal kidneys reveals features of hyperglycemic culture

Schumacher

Joris

Griensven

et al. 2023

Preprint

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Induced pluripotent stem cell (iPSC)-derived kidney organoids have the potential for a large variety of applications. However, they do not persist long in culture, for which reasons are still unclear. Furthermore, their morphological maturation, an essential feature for kidney function, has not been sufficiently assessed. Kidney organoids are transcriptionally much alike end-of-first-trimester fetal kidneys and present many of the same cell types. From large transmission electron microscopy tilescans of specific regions of interest, we compared the ultrastructures of iPSC-derived kidney organoids at various timepoints to human fetal kidneys of the first trimester. Unlike healthy fetal kidneys, large glycogen deposits developed over time in all organoid cell types, but particularly in podocytes and in chondrocytes, one of the off-target populations that contaminate the culture. Deeper investigation showed that glycogen synthase kinase 3b (GSK3b;) levels and activation were diminished over time, correlated with the accumulation of glycogen. Activated YAP was strongly expressed and large lipid droplets accumulated over time in proximal tubules. Accordingly, EGFR signaling increased significantly over time. Mitochondria in glomeruli and tubules contained few or no cristae, indicating mitochondrial damage. Together these features are known for hyperglycemic cultures and diabetic nephropathy. Measuring the glucose concentration in the kidney organoid culture medium showed a concentration of 2.94 g/mL, which is considered an elevated, pre-diabetic-like concentration in vitro. In summary, our ultrastructural assessment of iPSC-derived kidney organoids using an age-matched fetal human reference allowed the evaluation of cellular morphology, and we identified intracellular features that can inform the cellular state, which is particularly important while physiological testing of organoids is limited.

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“…Glucose, lipid and hormone metabolism disorders caused by HG exposure may lead to the accumulation of advanced glycation end products (AGEs) and the activation of protein kinase C (PKC) (18)(19)(20)(21)(22). AGEs can activate related signaling pathways, such as the nuclear factor kappa-B (NF-kB) and transforming growth factor b (TGF-b) pathways, promote EMT/EndMT, and result in glomerular podocyte loss and progressive glomerulosclerosis (23)(24)(25)(26)(27).…”

Section: Metabolism Disordersmentioning

confidence: 99%

Epigenetic modification in diabetic kidney disease

Liu

Wang

et al. 2023

Front. Endocrinol.

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Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefore, novel therapeutic methods, targets and biomarkers are urgently needed to meet clinical requirements. In recent years, increasing attention has been given to the role of epigenetic modification in the pathogenesis of DKD. Epigenetic variation mainly includes DNA methylation, histone modification and changes in the noncoding RNA expression profile, which are deeply involved in DKD-related inflammation, oxidative stress, hemodynamics, and the activation of abnormal signaling pathways. Since DKD is reversible at certain disease stages, it is valuable to identify abnormal epigenetic modifications as early diagnosis and treatment targets to prevent the progression of end-stage renal disease (ESRD). Because the current understanding of the epigenetic mechanism of DKD is not comprehensive, the purpose of this review is to summarize the role of epigenetic modification in the occurrence and development of DKD and evaluate the value of epigenetic therapies in DKD.

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Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease

Cited by 16 publications

References 94 publications

Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes

Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes

Ultrastructural comparison of human kidney organoids and human fetal kidneys reveals features of hyperglycemic culture

Epigenetic modification in diabetic kidney disease

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