Single-cell atlas reveals multi-faced responses of losartan on tubular mitochondria in diabetic kidney disease

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 21, 2025

Mitochondria are crucial to the function of renal tubular cells, and their dynamic perturbation in many aspects is an important mechanism diabetic kidney disease (DKD). Single-nucleus RNA sequencing (snRNA-seq) technology a high-throughput analysis technique for at level single cell nucleus. Here, our DKD mouse single-cell conveys more comprehensive mitochondrial profile, which helps us further understand therapeutic response this unique organelle family drugs. After high fat diet (HFD), mice were intraperitoneally injected with streptozotocin (STZ) induce DKD, then divided into three subsets: CON (healthy) subset, (vehicle) LST (losartan; 25 mg/kg/day) subset. Divide HK-2 LG (low glucose; 5 mM) HG (high 30 + 1 µ M) subsets. snRNA-seq was performed on tissues subset mice. To reveal effects losartan gene pathway changes mitochondria, Gene Ontology (GO) enrichment GSEA/GSVA scoring analyze specific proximal (PT) mitochondria treatment, including key events homeostasis such as morphology, dynamics, mitophagy, autophagic flux, respiratory chain, apoptosis, ROS generation. Preliminary validation through vitro vivo experiments, observation morphology dynamics using probes Mitotracker Red, evaluation effect electron microscopy, laser confocal immunofluorescence, Western blotting. Detection flux cells by transfecting Ad-mCherry-GFP-LC3B dual fluorescence labeled adenovirus. Various fluorescent energy detector used detect ROS, respiration mitochondrion. Through atlas kidneys, it found that treatment significantly increased percentage PT cells. differentially expressed genes showed autophagy mitochondrion pathway. Further GSEA GSVA revealed mitophagy other events, production, membrane potential, adenosine triphosphate (ATP) synthesis, involved protective thereby improving homeostasis. Consistent results also obtained cellular experiments. In addition, we highlighted subpopulation phenotype data, preliminarily validated co-localization expression Pink1 Gclc specimens patients treated losartan. Our research suggests scRNA-seq can reflect multifaceted landscape after drug these findings may provide new targets therapy level.

Language: Английский

---

ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 134(4)

Published: Dec. 5, 2023

Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we employed kidney-specific expression quantitative traits and single-nuclear open chromatin analysis to show that genetic variants linked dysfunction on chromosome 20 target acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2 knock-out mice, demonstrated their protection from fibrosis in multiple disease models. Our primary tubular cells revealed regulates de novo lipogenesis (DNL), causing NADPH depletion increasing ROS levels, ultimately leading NLRP3-dependent pyroptosis. Additionally, discovered pharmacological inhibition or ablation fatty acid synthase safeguarded against profibrotic gene prevented mice. Lipid accumulation genes related DNL were elevated kidneys patients with fibrosis. findings pinpoint as a critical reveal role disease.

Language: Английский

---

Chronic Kidney Disease Induced by Cadmium and Diabetes: A Quantitative Case-Control Study

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 9050 - 9050

Published: May 20, 2023

Kidney disease associated with chronic cadmium (Cd) exposure is primarily due to proximal tubule cell damage. This results in a sustained decline glomerular filtration rate (GFR) and tubular proteinuria. Similarly, diabetic kidney (DKD) marked by albuminuria declining GFR both may eventually lead failure. The progression diabetics exposed Cd has rarely been reported. Herein, we assessed the severity of proteinuria 88 controls, matched age, gender locality. overall mean blood excretion normalized creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L 0.0084 filtrate (0.96 µg/g creatinine), respectively. Tubular dysfunction, β2-microglobulin Ccr(Eβ2M/Ccr) was diabetes exposure. Doubling body burden, hypertension reduced estimated (eGFR) increased risks for severe dysfunction 1.3-fold, 2.6-fold, 84-fold, Albuminuria did not show significant association ECd/Ccr, but eGFR did. Hypertension 3-fold 4-fold increases risk albuminuria. These findings suggest that even low levels exacerbate diabetics.

Language: Английский

---

The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through ‘stacking’ of drugs from different classes

Diabetes Obesity and Metabolism, Journal Year: 2024, Volume and Issue: 26(6), P. 2046 - 2053

Published: March 22, 2024

Abstract Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression DKD to renal failure but, if utilized at an early enough stage DKD, also stabilize and/or reverse decline in function. The currently recognized standard for is blockade renin‐angiotensin system with angiotensin‐converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless a very stage, monotherapy these drugs will prevent and neither nor decompensation. Recently, addition sodium‐glucose cotransporter‐2 inhibitor mineralocorticoid blocker ACE ARBs has been clearly shown further decelerate use glucagon‐like peptide‐1 (GLP‐1) agonists promise decelerating DKD. Other that may aid deceleration are dipeptidyl peptidase‐4 inhibitors, pentoxifylline, statins, vasodilating beta blockers. Therefore, aggressive combinations (stacking) should improve preservation function

Language: Английский

---

Critical role of FGF21 in diabetic kidney disease: from energy metabolism to innate immunity

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 19, 2024

Diabetic kidney disease (DKD) stands as the predominant cause of chronic (CKD) on a global scale, with its incidence witnessing consistent annual rise, thereby imposing substantial burden public health. The pathogenesis DKD is primarily rooted in metabolic disorders and inflammation. Recent years have seen surge studies highlighting regulatory impact energy metabolism innate immunity, forging significant area research interest. Within this context, fibroblast growth factor 21 (FGF21), recognized an regulator, assumes pivotal role. Beyond role maintaining glucose lipid homeostasis, FGF21 exerts influence concurrently inhibiting inflammation fibrosis. Serving nexus between has evolved into therapeutic target for diabetes, nonalcoholic steatohepatitis, cardiovascular diseases. While relationship garnered increased attention recent studies, comprehensive exploration association yet to be systematically addressed. This paper seeks fill gap by summarizing mechanisms through which operates DKD, encompassing facets immunity. Additionally, we aim assess diagnostic prognostic value explore potential treatment modality condition.

Language: Английский

---