bims-raghud 2024-06-16 papers

Issue of 2024–06–16
three papers selected by
Irene Sambri, TIGEM

JCI Insight. 2024 Jun 10. pii: e168825. [Epub ahead of print]9(11):

Glycolytic lactate in diabetic kidney disease.

Kidney Precision Medicine Project, and the CRIC Study Investigators

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Keywords: Chronic kidney disease; Diabetes; Mitochondria; Nephrology

DOI: https://doi.org/10.1172/jci.insight.168825

bioRxiv. 2024 May 31. pii: 2024.05.27.595830. [Epub ahead of print]

Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution.

Yoshiharu Muto, Yasuhiro Yoshimura, Haojia Wu, Monica Chang-Panesso, Nicolas Ledru, Owen M Woodward, Patricia Outeda, Tao Cheng, Moe R Mahjoub, Terry J Watnick, Benjamin D Humphreys.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalogue differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.

DOI: https://doi.org/10.1101/2024.05.27.595830

Stem Cell Res. 2024 Jun 05. pii: S1873-5061(24)00165-X. [Epub ahead of print]78 103467

Establishment of a human induced pluripotent stem cell line from a patient with dilated cardiomyopathy.

Lingqun Ye, Baoqiang Ni, Hongchun Wu, Xinglong Han, Huadong Li, Junwei Liu, Shijun Hu, Wei Lei.

Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in dozens of cardiac genes have been connected to the development of DCM including the Troponin T2 gene (TNNT2). Here, we generated a human induced pluripotent stem cells (hiPSCs) from a DCM patient with a familial history that carries a missense mutation in TNNT2. The hiPSCs show typical morphology of pluripotent stem cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers.

DOI: https://doi.org/10.1016/j.scr.2024.103467