SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(5)

Published: Jan. 13, 2023

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, healthy controls (HCs). Participants T2D obese had higher estimated glomerular filtration rates mesangial volumes than HCs. Ten participants been prescribed SGLT2i (T2Di[+]) 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster highest T2Di(-) patients. However, transcriptional alterations treatment seen across nephron segments, particularly distal nephron. was associated suppression transcripts glycolysis, gluconeogenesis, tricarboxylic acid cycle pathways PT, but opposite effect thick ascending limb. Transcripts energy-sensitive mTORC1-signaling pathway returned toward HC levels all segments T2Di(+), consistent a mouse model treated SGLT2i. Decreased phosphorylated S6 protein tubules T2Di(+) patients confirmed changes mTORC1 activity. We propose that benefits kidneys mitigating diabetes-induced metabolic perturbations via signaling tubules.

Language: Английский

Chronic kidney disease

Nature Reviews Disease Primers, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 30, 2025

Language: Английский

The Renal Pathology of Obesity

Kidney International Reports, Journal Year: 2017, Volume and Issue: 2(2), P. 251 - 260

Published: Jan. 23, 2017

Obesity causes various structural, hemodynamic, and metabolic alterations in the kidney. Most of these are likely to be compensatory responses systemic increase demand that is seen with obesity. In some cases, however, renal injury becomes clinically apparent as a result failure. Obesity-related glomerulopathy best known such disease states. Factors may sensitize obese individuals failure associated include severity number obesity-associated conditions or complications, including components syndrome, mismatch body size nephron mass, due reductions congenital acquired origin.

Language: Английский

The ageing kidney: Molecular mechanisms and clinical implications

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 63, P. 101151 - 101151

Published: Aug. 21, 2020

As human life expectancy keeps increasing, ageing populations present a growing challenge for clinical practices. Human is associated with molecular, structural, and functional changes in variety of organ systems, including the kidney. During process, kidney experiences progressive decline as well macroscopic microscopic histological alterations, which are accentuated by systemic comorbidities like hypertension diabetes mellitus, or preexisting underlying diseases. Although per se does not cause injury, physiologic normal processes likely to impair reparative capacity thus predispose older people acute disease, chronic disease other renal Mechanistically, cell senescence plays key role ageing, involving number cellular signaling mechanisms, many may be harnessed international targets slowing even reversing ageing. This review summarizes characteristics highlights latest progresses deciphering envisages potential interventional strategies novel therapeutic preventing improving hope maintaining long-term health function across course.

Language: Английский

APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease

Journal of the American Society of Nephrology, Journal Year: 2016, Volume and Issue: 27(12), P. 3600 - 3610

Published: March 29, 2016

APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury unknown. Because is unique to humans and some primates, we created transgenic (Tg) mice using promoter nephrin-encoding Nphs1 express reference sequence (G0) or G2 variant podocytes, establishing Tg lines a spectrum expression levels. Podocytes from Tg-G0 Tg-G2 did not undergo necrosis, apoptosis, autophagic cell death vivo, even highly expressed transgenes. Further, develop pathology, proteinuria, azotemia as 300 days age. However, by 200 age, had significantly lower podocyte density than age-matched WT had, difference that was evident at weaning. Notably, pregnancy-associated phenotype encompassed eclampsia, preeclampsia, fetal/neonatal deaths, small litter sizes occurred more severely mice. Similar human placenta, placentas APOL1. Overall, these results suggest depletion could predispose individuals genotypes response second stressor, add other published evidence associating preeclampsia.

Language: Английский

The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age

Kidney International, Journal Year: 2017, Volume and Issue: 91(5), P. 1126 - 1145

Published: Jan. 5, 2017

Language: Английский

Organoid single cell profiling identifies a transcriptional signature of glomerular disease

JCI Insight, Journal Year: 2019, Volume and Issue: 4(1)

Published: Jan. 10, 2019

Podocyte injury is central to many forms of kidney disease, but transcriptional signatures reflecting podocyte and compensation mechanisms are challenging analyze in vivo. Human organoids derived from pluripotent stem cells (PSCs), a potentially new model for disease regeneration, present an opportunity explore the plasticity podocytes. Here, profiling more than 12,000 single human PSC–derived organoid cultures was used identify robust reproducible cell lineage gene expression shared with developing kidneys based on trajectory analysis. Surprisingly, signature characteristic glomerular epithelial also observed tissue cohort. This correlated proteinuria inverse eGFR, it confirmed independent podocytopathy Three genes particular were further characterized as novel components signature. We conclude that reliably recapitulate developmental program podocytes other lineages profiles seen reactivated disease. Our findings demonstrate approach identifying molecular programs involved pathogenesis glomerulopathies.

Language: Английский

mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

JCI Insight, Journal Year: 2019, Volume and Issue: 4(18)

Published: Sept. 18, 2019

The cellular origins of glomerulosclerosis involve activation parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target rapamycin-mediated (mTOR-mediated) hypertrophy is recognized as an important signaling pathway in the context glomerular disease, role a compensatory mechanism preventing PEC remains poorly understood. In this study, we show that mTOR activation-related genes were both upregulated intercorrelated biopsies from patients with focal segmental (FSGS) diabetic nephropathy, suggesting pathological roles. Advanced morphometric analyses murine human tissues identified aiming to regulate functional integrity response somatic growth, depletion, even - all absence detectable regeneration. mice, pharmacological inhibition during acute loss impaired remaining podocytes, resulting unexpected albuminuria, activation, glomerulosclerosis. Exacerbated persistent enabled vicious cycle limit its beneficial effects. summary, our data highlight critical protective mTOR-mediated following order preserve integrity,

Language: Английский

Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss

Journal of the American Society of Nephrology, Journal Year: 2020, Volume and Issue: 31(4), P. 865 - 875

Published: March 3, 2020

Significance Statement In males with classic Fabry disease, the processes leading to frequent outcome of ESKD are poorly understood. Mutations in gene encoding α -galactosidase A leads globotriaosylceramide accumulation various cell types; podocytes, this progresses age. study 55 disease genotype and/or phenotype, authors found an increasing fraction podocyte cytoplasm occupied by globotriaosylceramide, which plateaued at around age 27 years. At same time, volume continued rise, apparently expense stress (indicated foot process width) and loss. These changes associated urinary protein excretion, a strong prognosticator adverse renal outcomes, reduction GFR, indicating need for early intervention before critical Background Defects lead (GL3) types. glomerular GL3 Of concern, podocytes relatively resistant enzyme replacement therapy replicating, little ability compensate Methods (mean years) we performed unbiased quantitative morphometric electron microscopic studies biopsied kidney samples from patients seven living transplant donors (to serve as controls). We extracted clinical information medical records trial databases. Results Podocyte (proportion GL3) increased up about 27, suggesting that beyond threshold may compromise survival these cells. was injury loss, evidenced width (a generally accepted structural marker injury) decreased number density per volume. Worsening parameters (increasing also excretion—a outcomes disease—as well decreasing GFR. Conclusions Given known association between loss irreversible FSGS global glomerulosclerosis, points important role progression nephropathy indicates therapeutic occurs.

Language: Английский

Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 11, 2020

Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed a state of accelerated premature aging. Aging share common characteristic features with increased cellular senescence, conserved program characterized by an irreversible cell cycle arrest altered transcriptome secretome. While developmental senescence acute may positively contribute to the fine-tuning embryogenesis injury repair, when unresolved promptly, plays crucial role in fibrogenesis progression. Senescent cells elicit their fibrogenic actions primarily secreting assortment inflammatory profibrotic factors known senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent could promising new target for therapeutic intervention senotherapy, which includes depleting cells, modulating SASP restoration inhibitors. this review, we discuss current understanding mechanism fibrosis. We also highlight potential options targeting treatment CKD.

Language: Английский