scholarly journals Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1580
Author(s):  
Leslie S. Gewin
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Fatty Acid Oxidation ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Acid Oxidation ◽  
Renal Tubules ◽  
Solute Movement ◽  
Renal Tubular

The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression.

scholarly journals Increased Fatty Acid Oxidation in Differentiated Proximal Tubular Cells Surviving a Reversible Episode of Acute Kidney Injury

2018 ◽  
Vol 47 (4) ◽  
pp. 1338-1351 ◽  
Author(s):  
Aurélien Bataille ◽  
Pierre Galichon ◽  
Nadjim Chelghoum ◽  
Badreddine Mohand Oumoussa ◽  
Marie-Julia Ziliotis ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
High Throughput ◽  
Renal Fibrosis ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Acid Oxidation ◽  
Renal Tubules ◽  
Sham Surgery

Background/Aims: Fatty acid oxidation (FAO), the main source of energy produced by tubular epithelial cells in the kidney, was found to be defective in tubulo-interstitial samples dissected out in kidney biopsies from patients with chronic kidney disease (CKD). Experimental data indicated that this decrease was a strong determinant of renal fibrogenesis, hence a focus for therapeutic interventions. Nevertheless, whether persistently differentiated renal tubules, surviving in a pro-fibrotic environment, also suffer from a decrease in FAO, is currently unknown. Methods: To address this question, we isolated proximal tubules captured ex vivo on the basis of the expression of an intact brush border antigen (Prominin-1) in C57BL6/J mice subjected to a controlled, two-hit model of renal fibrosis (reversible ischemic acute kidney injury (AKI) or sham surgery, followed by angiotensin 2 administration). A transcriptomic high throughput sequencing was performed on total mRNA from these cells, and on whole kidneys. Results: In contrast to mice subjected to sham surgery, mice with a history of AKI displayed histologically more renal fibrosis when exposed to angiotensin 2. High throughput RNA sequencing, principal component analysis and clustering showed marked consistency within experimental groups. As expected, FAO transcripts were decreased in whole fibrotic kidneys. Surprisingly, however, up- rather than down-regulation of metabolic pathways (oxidative phosphorylation, fatty acid metabolism, glycolysis, and PPAR signalling pathway) was a hallmark of the differentiated tubules captured from fibrotic kidneys. Immunofluorescence co-staining analysis confirmed that the expression of FAO enzymes was dependent of tubular trophicity. Conclusions: These data suggest that in differentiated proximal tubules energetic hyperactivity is promoted concurrently with organ fibrogenesis.

scholarly journals Proximal Tubular Oxidative Metabolism in Acute Kidney Injury and the Transition to Chronic Kidney Disease

Kidney360 ◽  
2020 ◽  
pp. 10.34067/KID.0004772020
Author(s):  
Jennifer A. Schaub ◽  
Manjeri A. Venkatachalam ◽  
Joel M. Weinberg
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Oxidative Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Kidney Injury ◽  
Therapeutic Interventions ◽  
Acid Oxidation ◽  
Atp Production

The proximal tubule relies on oxidative mitochondrial metabolism to meet its energy needs and has limited capacity for glycolysis, which makes it uniquely susceptible to damage during Acute Kidney Injury, especially after ischemia and anoxia. In that setting, mitochondrial ATP production is initially decreased by several mechanisms, including fatty acid-induced uncoupling and inhibition of respiration related to changes in the shape and volume of mitochondria. Glycolysis initially is insufficient as a source of ATP to protect the cells and mitochondrial function, but supplementation of tricarboxylic acid cycle intermediates, augments anaerobic ATP production and improves recovery of mitochondrial oxidative metabolism. Incomplete recovery is characterized by defects of respiratory enzymes and lipid metabolism. During the transition to Chronic Kidney Disease (CKD), tubular cells atrophy but maintain high expression of glycolytic enzymes and there is decreased fatty acid oxidation. These metabolic changes may be amenable to a number of therapeutic interventions.

scholarly journals Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Bohan Chen ◽  
Pei Wang ◽  
Xianhui Liang ◽  
Chunming Jiang ◽  
Yan Ge ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Binding Protein ◽  
Renal Tubules ◽  
Genetic Ablation ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Renal Fibrogenesis ◽  
Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

Abstract 188: Loss of Renal Prolyl Carboxypeptidase in Mice With Chronic Kidney Disease

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Orly Leiva ◽  
Khalid M Elased ◽  
Mariana Morris ◽  
Nadja Grobe
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Expression ◽  
Western Blot ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Left Renal Artery ◽  
Renal Tubules ◽  
Ang Ii ◽  
Chronic Kidney Injury

There are 26 million adults with chronic kidney disease (CKD) in the U.S. and the incidence continues to increase. It is well documented that the activation of the renin angiotensin system and the elevated formation of angiotensin (Ang) II both contribute to renal pathophysiology in CKD. Emerging evidence suggests that the Ang II degrading protease prolyl carboxypeptidase (PCP) is renoprotective. Thus, we investigated protein expression and activity of renal PCP using immunofluorescence, western blot and mass spectrometry in a mouse model of CKD. Renal injury in male C57Bl6 mice was caused by constriction of the left renal artery using silver clips (2K1C-method). Blood pressure measurements by radiotelemetry revealed a significant increase of 36.1 ± 3.9 mm Hg in 2K1C animals compared with control animals 1 week after clip placement (p<0.0001). Using immunofluorescence and confocal microscopy, PCP was localized in the Bowman’s capsule of the glomerulus and in proximal and distal renal tubules. Western blot analysis showed PCP was significantly reduced in clipped 2K1C kidneys compared to unclipped kidneys of the 2K1C mice or compared to control mice (clipped 0.04 ± 0.02 vs unclipped 0.58 ± 0.16 vs control 0.65 ± 0.18, p < 0.05). In addition, renal PCP enzyme activity was found to be markedly reduced in 2K1C kidneys as assessed by mass spectrometric based enzyme assays (clipped 37.1 ± 4.3 pmol Ang-(1-7)/h/μg vs unclipped 77.3 ± 12.3 pmol Ang-(1-7)/h/μg vs control 120.7 ± 14.7 pmol Ang-(1-7)/h/μg, p < 0.01). In contrast, protein expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected. Notably, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion (clipped 34.6 ± 3.1 vs unclipped 52.1 ± 4.0 vs control 1.2 ± 2.1, p < 0.0001) and renal fibrosis (clipped 57.5 ± 0.9 vs unclipped 33.0 ± 0.7 vs control 3.3 ± 0.2, p < 0.0001). Results suggest that PCP is suppressed in chronic kidney injury and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PCP. Therefore, Ang II processing by PCP may have clinical implications in patients with renal pathologies.

Reduced urinary corin levels in patients with chronic kidney disease

2013 ◽  
Vol 124 (12) ◽  
pp. 709-717 ◽  
Author(s):  
Chaodong Fang ◽  
Lei Shen ◽  
Liang Dong ◽  
Meng Liu ◽  
Sensen Shi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Human Urine ◽  
Animal Studies ◽  
Kidney Tissue ◽  
Renal Tubules ◽  
Tissue Samples ◽  
Protein Levels ◽  
Normal Individuals ◽  
Renal Tubular

Corin is a cardiac protease that regulates BP (blood pressure) by activating natriuretic peptides. Recent animal studies identified corin expression in the kidney where it may regulate renal function. In the present study, we tested the hypothesis that corin may be present in human urine and that urinary corin levels may be altered in patients with kidney disease. We obtained urine and kidney tissue samples from normal individuals and CKD (chronic kidney disease) patients. Using ELISA, we detected corin protein in human urine. In normal individuals, urinary corin levels did not correlate with that of plasma, indicating that urinary corin is probably of kidney origin. Compared with normal controls, CKD patients had markedly reduced urinary corin levels and this reduction correlated with disease severity. By immunostaining, human corin protein was identified on the epithelial cell surface in renal tubules. The renal corin mRNA and protein levels were significantly lower in CKD patients than non-CKD controls. The results indicate that renal tubular corin may be shed into urine and that urinary and renal corin levels were reduced in CKD patients. These data suggest that reduced corin levels in the kidney may reflect the underlying pathology in CKD.

scholarly journals Clinical Usefulness of Urinary Liver Fatty Acid-Binding Protein Excretion for Predicting Acute Kidney Injury during the First 7 Days and the Short-Term Prognosis in Acute Heart Failure Patients with Non-Chronic Kidney Disease

2017 ◽  
Vol 7 (4) ◽  
pp. 301-315 ◽  
Author(s):  
Akihiro Shirakabe ◽  
Noritake Hata ◽  
Nobuaki Kobayashi ◽  
Hirotake Okazaki ◽  
Masato Matsushita ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Fatty Acid Binding Protein ◽  
Kidney Injury ◽  
Liver Fatty Acid ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

Background: The clinical significance of urinary liver fatty acid-binding protein (u-LFABP) in acute heart failure (AHF) patients remains unclear. Methods and Results: The u-LFABP levels on admission of 293 AHF patients were analyzed. The patients were divided into 2 groups according to the u-LFABP quartiles (Q1, Q2, and Q3 = low u-LFABP [L] group vs. Q4 = high u-LFABP [H] group). We evaluated the diagnostic and prognostic value of u-LFABP and compared the findings between the chronic kidney disease (CKD; n = 165) and non-CKD patients (n = 128). Acute kidney injury (AKI) during the first 7 days was evaluated based on the RIFLE criteria. In the non-CKD group, the number of AKI patients during the first 7 days was significantly greater in the H group (70.0%) than in the L group (45.6%). A multivariate logistic regression model indicated that the H group (odds ratio: 3.850, 95% confidence interval [CI] 1.128-13.140) was independently associated with AKI during the first 7 days. The sensitivity and specificity of u-LFABP for predicting AKI were 63.6 and 59.7% (area under the ROC curve 0.631) at 41.9 ng/mg × cre. A Cox regression model identified the H group (hazard ratio: 13.494, 95% CI 1.512-120.415) as an independent predictor of the 60-day mortality. A Kaplan-Meier curve, including all-cause death within 60 days, showed a significantly poorer survival rate in the H group than in the L group (p = 0.036). Conclusions: The u-LFABP level is an effective biomarker for predicting AKI during the first 7 days of hospitalization and an adverse outcome in AHF patients with non-CKD.

scholarly journals Berberine Reduces Lipid Accumulation by Promoting Fatty Acid Oxidation in Renal Tubular Epithelial Cells of the Diabetic Kidney

2022 ◽  
Vol 12 ◽  
Author(s):  
Qingfeng Rong ◽  
Baosheng Han ◽  
Yafeng Li ◽  
Haizhen Yin ◽  
Jing Li ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Fatty Acid Oxidation ◽  
High Glucose ◽  
Lipid Accumulation ◽  
Diabetic Kidney Disease ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Diabetic Kidney ◽  
Renal Tubular

Abnormal lipid metabolism in renal tubular epithelial cells contributes to renal lipid accumulation and disturbed mitochondrial bioenergetics which are important in diabetic kidney disease. Berberine, the major active constituent of Rhizoma coptidis and Cortex phellodendri, is involved in regulating glucose and lipid metabolism. The present study aimed to investigate the protective effects of berberine on lipid accumulation in tubular epithelial cells of diabetic kidney disease. We treated type 2 diabetic db/db mice with berberine (300 mg/kg) for 12 weeks. Berberine treatment improved the physical and biochemical parameters of the db/db mice compared with db/m mice. In addition, berberine decreased intracellular lipid accumulation and increased the expression of fatty acid oxidation enzymes CPT1, ACOX1 and PPAR-α in tubular epithelial cells of db/db mice. The mitochondrial morphology, mitochondrial membrane potential, cytochrome c oxidase activity, mitochondrial reactive oxygen species, and mitochondrial ATP production in db/db mice kidneys were significantly improved by berberine. Berberine intervention activated the AMPK pathway and increased the level of PGC-1α. In vitro berberine suppressed high glucose-induced lipid accumulation and reversed high glucose-induced reduction of fatty acid oxidation enzymes in HK-2 cells. Importantly, in HK-2 cells, berberine treatment blocked the change in metabolism from fatty acid oxidation to glycolysis under high glucose condition. Moreover, berberine restored high glucose-induced dysfunctional mitochondria. These data suggested that berberine alleviates diabetic renal tubulointerstitial injury through improving high glucose-induced reduction of fatty acid oxidation, alleviates lipid deposition, and protect mitochondria in tubular epithelial cells.

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