Background: The renal tubules, which have distant metabolic features and functions in different segments, reabsorb >99% of approximately 180 l of water and 25,000 mmol of Na daily. Defective metabolism in renal tubules is involved in the pathobiology of kidney diseases. However, the mechanisms underlying the metabolic regulation in renal tubules remain to be defined.
Methods: We quantitatively compared the proteomes of the isolated proximal tubules (PT) and distal tubules (DT) from C57BL/6 mouse using tandem mass tag (TMT) labeling-based quantitative mass spectrometry. Bioinformatics analysis of the differentially expressed proteins revealed the significant differences between PT and DT in metabolism pathway. We also performed in vitro and in vivo assays to investigate the molecular mechanism underlying the distant metabolic features in PT and DT.
Findings: We demonstrate that the renal proximal tubule (PT) has high expression of lipid metabolism enzymes, which is transcriptionally upregulated by abundantly expressed PPARα/γ. In contrast, the renal distal tubule (DT) has elevated glycolytic enzyme expression, which is mediated by highly expressed c-Myc. Importantly, PPARγ transcriptionally enhances the protease iRhom2 expression in PT, which suppresses EGF expression and secretion and subsequent EGFR-dependent glycolytic gene expression and glycolysis. PPARγ inhibition reduces iRhom2 expression and increases EGF and GLUT1 expression in PT in mice, resulting in renal tubule hypertrophy, tubulointerstitial fibrosis and damaged kidney functions, which are rescued by 2-deoxy-d-glucose treatment.
Interpretation: These findings delineate instrumental mechanisms underlying the active lipid metabolism and suppressed glycolysis in PT and active glycolysis in DT and reveal critical roles for PPARs and c-Myc in maintaining renal metabolic homeostasis. FUND: This work was supported by the National Natural Science Foundation of China (grants 81572076 and 81873932; to Q.Z.), the Applied Development Program of the Science and Technology Committee of Chongqing (cstc2014yykfB10003; Q.Z.), the Program of Populace Creativities Workshops of the Science and Technology Committee of Chongqing (Q.Z.), the special demonstration programs for innovation and application of techniques (cstc2018jscx-mszdX0022) from the Science and Technology Committee of Chongqing (Q.Z.).
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http://dx.doi.org/10.1016/j.ebiom.2018.10.072 | DOI Listing |
J Biophotonics
January 2025
State Key Laboratory of Extreme Photonics and Instrumentations, Centre for Optical and Electromagnetic Research, College of Optical Science and Engineering, International Research Center for Advanced Photonics, Zhejiang University, Hangzhou, China.
Three-photon fluorescence (3PF) microscopy encounters significant challenges in biological research and clinical applications, primarily due to the limited availability of high-performance probes. We took a shortcut by exploring the excellent 3PF property of berberine hydrochloride (BH), a clinically utilized drug derived from the traditional Chinese medicine, Coptis. Capitalizing on its renal metabolism characteristics, we employed BH for in vivo 3PF microscopic imaging of the mouse kidney.
View Article and Find Full Text PDFFront Med (Lausanne)
January 2025
Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, Guangdong, China.
Objective: The effectiveness of using as an adjuvant therapy for patients with renal dysfunction (RD), especially acute kidney injury (AKI), is still a topic of debate. In response to the current conflicting data, the present meta-analysis was conducted to assess the clinical effectiveness of in the treatment of RD and to provide evidence for clinical practice.
Methods: Several databases, including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang, were systematically searched updated to March 25, 2024.
Front Med (Lausanne)
January 2025
Department of Internal Medicine, Texas Tech University Health Sciences Centre, Lubbock, TX, United States.
While changes in glomerular function and structure may herald diabetic kidney disease (DKD), many studies have underscored the significance of tubule-interstitial changes in the progression of DKD. Indeed, tubule-interstitial fibrosis may be the most important determinant of progression of DKD as in many forms of chronic glomerulopathies. The mechanisms underlying the effects of tubular changes on glomerular function in DKD have intrigued many investigators, and therefore, the signaling mechanisms underlying the cross-talk between tubular cells and glomerular cells have been the focus of investigation in many recent studies.
View Article and Find Full Text PDFJ Transl Med
January 2025
Department of Endocrine Medicine, Shanghai Sixth People's Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201306, Chin, China.
Background And Objective: Mitochondria are crucial to the function of renal tubular cells, and their dynamic perturbation in many aspects is an important mechanism of diabetic kidney disease (DKD). Single-nucleus RNA sequencing (snRNA-seq) technology is a high-throughput sequencing analysis technique for RNA at the level of a single cell nucleus. Here, our DKD mouse kidney single-cell RNA sequencing conveys a more comprehensive mitochondrial profile, which helps us further understand the therapeutic response of this unique organelle family to drugs.
View Article and Find Full Text PDFBiochem Biophys Res Commun
January 2025
Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Electronic address:
SLC17A3 localized to the apical membrane of the renal proximal tubules has been implicated in the urinary excretion of drugs and endogenous/exogenous metabolites transported into the tubules by OAT1 and OAT3. Because SLC17A3 mediates the facilitated diffusion of organic anions, which requires a sensitive and rapid assay, no system has been established to evaluate its transport activity in mammalian cells. In this study, we demonstrated that the exposure of cells expressing click beetle luciferase (bLuc) and SLC17A3 to D-luciferin produces marked bioluminescence, which enables the evaluation of SLC17A3 function.
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