Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury

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.

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MO328ASYMPTOMATIC HYPERURICEMIA ACTS AS ANTIOXIDANT DURING ACUTE KIDNEY INJURY AND DISEASE*

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab084.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Qiuyue Ma ◽

Viviane Gnemmi ◽

Anders Hans-Joachim ◽

Stefanie Steiger

Keyword(s):

Acute Kidney Injury ◽

Fatty Acid ◽

Epithelial Cells ◽

Kidney Function ◽

Metabolic Activity ◽

Mitochondrial Biogenesis ◽

Kidney Injury ◽

Acid Oxidation ◽

Tubular Epithelial Cells ◽

Tubular Injury

Abstract Background and Aims Acute kidney injury (AKI) and disease (AKD) are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function. While there is no doubt that crystalline uric acid (UA) causes acute and chronic UA nephropathy, urolithiasis and kidney stone disease, the pathogenesis of asymptomatic HU in AKI/AKD is incompletely understood. In animal studies, elevated serum UA levels may lead to endothelial dysfunction, renin-angiotensin system activation and oxidative stress. However, such models do not mimic human HU. To overcome this issue, we established a model of AKI/AKD with clinically relevant serum UA levels and hypothesized that asymptomatic HU improves the outcomes after AKI/AKD by restoring metabolic activity and mitochondrial biogenesis in macrophages and tubular epithelial cells. Method Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet enriched with inosine. Hyperuricemic mice (serum UA ≥7 mg/dL) and mice without HU (serum UA 4-5 mg/dL) underwent uninephrectomy followed by unilateral ischemia-reperfusion (IR) to induce AKI/AKD. Serum and kidneys were collected on day 3 and 14 after AKI/AKD, and kidney function, tubular injury, inflammation, mitochondrial dysfunction, metabolic activity (fatty acid oxidation) and macrophage infiltration were quantified using GFR measurement, immunohistochemistry, colorimetric assays, electron microscopy, RT-PCR and flow cytometry. Results We observed an increase in serum UA levels from 7 to 10 mg/dL in hyperuricemic mice on day 3 after IR-induced AKI/AKD that returned to 7 mg/dL after 14 days (Figure left). While there was no difference in GFR between hyperuricemic and mice without HU with AKI/AKD on day 3, we found an improved kidney function in hyperuricemic mice on day 14 (Figure middle). This was associated with significantly less tubular injury and inflammation as well as an increase in the number of infiltrating anti-inflammatory M2-like macrophages as compared to mice without HU. Intrarenal mRNA expression level of the pro-oxidant heme-oxygenase-1 was reduced in hyperuricemic mice. However, the expression of anti-oxidant enzymes (Nrf-1 and Sod) and metabolic genes associated with fatty acid oxidation (Cpt1, Pparg, and Pgc1b) significantly increased as compared to mice without HU 14 days after AKI/AKD. In addition, HU increased the number of phospho-Histone-3 and intact proximal tubules and restored tubular mitochondrial morphology as indicated by an increased mitochondrial aspect ratio (Figure right). Conclusion Our data imply that asymptomatic HU improves kidney outcomes after IR-induced AKI/AKD because HU attenuates tubular injury and inflammation. In addition, we found that HU enhances the metabolic activity and anti-inflammatory M2-like macrophage polarization as well as restores mitochondrial biogenesis in tubular epithelial cells, suggesting that HU acts as antioxidant by improving kidney recovery after AKI/AKD.

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Pathogenesis of Acute Kidney Injury

Kidney Protection ◽

10.1093/med/9780190611620.003.0002 ◽

2019 ◽

pp. 11-20

Author(s):

David P. Basile ◽

Babu J. Padanilam

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Renal Function ◽

Fatty Acid ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Acid Oxidation ◽

Clinical Disorder ◽

Successful Recovery ◽

Multiple Issues

Acute kidney injury represents a significant clinical disorder associated with a rapid loss of renal function following a variety of potential insults. This chapter reviews multiple issues related to the pathophysiology of AKI with an emphasis on studies from animal models. Early responses following kidney injury include impaired hemodynamic and bioenergetic responses. Reductions in renal ATP levels occur as a result of compromised fatty acid oxidation and impaired compensation by glycolysis. Sustained reductions in perfusion contribute to extension of AKI characterized by complex inflammatory and cellular injury responses, often leading to cell death. Concurrently, the kidney displays an elegant repair response, leading to successful recovery in most cases, characterized in part by epithelial cell growth, while maladaptive or incomplete recovery of tubules or capillaries can predispose the development of interstitial fibrosis and CKD progression.

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Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation.

Kidney International ◽

10.1016/j.kint.2021.08.031 ◽

2021 ◽

Author(s):

Sian E. Piret ◽

Ahmed A. Attallah ◽

Xiangchen Gu ◽

Yiqing Guo ◽

Nehaben A. Gujarati ◽

...

Keyword(s):

Transcription Factor ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Kidney Injury ◽

Acid Oxidation ◽

Proximal Tubular

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Sirtuin 5 Regulates Proximal Tubule Fatty Acid Oxidation to Protect against AKI

Journal of the American Society of Nephrology ◽

10.1681/asn.2019020163 ◽

2019 ◽

Vol 30 (12) ◽

pp. 2384-2398 ◽

Cited By ~ 7

Author(s):

Takuto Chiba ◽

Kevin D. Peasley ◽

Kasey R. Cargill ◽

Katherine V. Maringer ◽

Sivakama S. Bharathi ◽

...

Keyword(s):

Fatty Acid ◽

Epithelial Cells ◽

Proximal Tubule ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Tubular Epithelial Cells ◽

Peroxisomal Fatty Acid Oxidation ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Peroxisomal Fatty Acid

BackgroundThe primary site of damage during AKI, proximal tubular epithelial cells, are highly metabolically active, relying on fatty acids to meet their energy demands. These cells are rich in mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Emerging evidence shows that both fatty acid pathways are regulated by reversible posttranslational modifications, particularly by lysine acylation. Sirtuin 5 (Sirt5), which localizes to both mitochondria and peroxisomes, reverses post-translational lysine acylation on several enzymes involved in fatty acid oxidation. However, the role of the Sirt5 in regulating kidney energy metabolism has yet to be determined.MethodsWe subjected male Sirt5-deficient mice (either +/− or −/−) and wild-type controls, as well as isolated proximal tubule cells, to two different AKI models (ischemia-induced or cisplatin-induced AKI). We assessed kidney function and injury with standard techniques and measured fatty acid oxidation by the catabolism of 14C-labeled palmitate to 14CO2.ResultsSirt5 was highly expressed in proximal tubular epithelial cells. At baseline, Sirt5 knockout (Sirt5−/−) mice had modestly decreased mitochondrial function but significantly increased fatty acid oxidation, which was localized to the peroxisome. Although no overt kidney phenotype was observed in Sirt5−/− mice, Sirt5−/− mice had significantly improved kidney function and less tissue damage compared with controls after either ischemia-induced or cisplatin-induced AKI. This coincided with higher peroxisomal fatty acid oxidation compared with mitochondria fatty acid oxidation in the Sirt5−/− proximal tubular epithelial cells.ConclusionsOur findings indicate that Sirt5 regulates the balance of mitochondrial versus peroxisomal fatty acid oxidation in proximal tubular epithelial cells to protect against injury in AKI. This novel mechanism might be leveraged for developing AKI therapies.

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The Link Between the Mitochondrial Fatty Acid Oxidation Derangement and Kidney Injury

Frontiers in Physiology ◽

10.3389/fphys.2020.00794 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lara Console ◽

Mariafrancesca Scalise ◽

Nicola Giangregorio ◽

Annamaria Tonazzi ◽

Maria Barile ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Kidney Injury ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

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

Kidney360 ◽

10.34067/kid.0004772020 ◽

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.

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

Nutrients ◽

10.3390/nu13051580 ◽

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.

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