Dataset Information

Metabolomic changes in cats with renal disease and calcium oxalate uroliths.

ABSTRACT:

Introduction

There is a significant incidence of cats with renal disease (RD) and calcium oxalate (CaOx) kidney uroliths in domesticated cats. Foods which aid in the management of these diseases may be enhanced through understanding the underlying metabolomic changes.

Objective

Assess the metabolomic profile with a view to identifying metabolomic targets which could aid in the management of renal disease and CaOx uroliths.

Method

This is a retrospective investigation of 42 cats: 19 healthy kidney controls, 11 with RD, and 12 that formed CaOx nephroliths. Cats were evaluated as adults (2 through 7 years) and at the end of life for plasma metabolomics, body composition, and markers of renal dysfunction. Kidney sections were assessed by Pizzolato stain at the end of life for detection of CaOx crystals. CaOx stone presence was also assessed by analysis of stones removed from the kidney at the end of life.

Results

There were 791 metabolites identified with 91 having significant (p < 0.05, q < 0.1) changes between groups. Many changes in metabolite concentrations could be explained by the loss of renal function being most acute in the cats with RD while the cats with CaOx stones were intermediate between control and RD (e.g., urea, creatinine, pseudouridine, dimethylarginines). However, the concentrations of some metabolites differentiated RD from CaOx stone forming cats. These were either increased in the RD cats (e.g., cystathionine, dodecanedioate, 3-(3-amino-3-carboxypropyl) uridine, 5-methyl-2'-deoxycytidine) or comparatively increased in the CaOx stone forming cats (phenylpyruvate, 4-hydroxyphenylpyruvate, alpha-ketobutyrate, retinal).

Conclusions

The metabolomic changes show specific metabolites which respond generally to both renal diseases while the metabolomic profile still differentiates cats with RD and cats with CaOx uroliths.

SUBMITTER: Jewell DE

PROVIDER: S-EPMC9374649 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Metabolomic changes in cats with renal disease and calcium oxalate uroliths.

Jewell Dennis E DE Tavener Selena K SK Hollar Regina L RL Panickar Kiran S KS

Metabolomics : Official journal of the Metabolomic Society 20220813 8

<h4>Introduction</h4>There is a significant incidence of cats with renal disease (RD) and calcium oxalate (CaOx) kidney uroliths in domesticated cats. Foods which aid in the management of these diseases may be enhanced through understanding the underlying metabolomic changes.<h4>Objective</h4>Assess the metabolomic profile with a view to identifying metabolomic targets which could aid in the management of renal disease and CaOx uroliths.<h4>Method</h4>This is a retrospective investigation of 42 ...[more]

PMID: 35962261

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Project description:BackgroundNephrolithiasis, a common urinary system disorder, exhibits high morbidity and recurrence rates, correlating with renal dysfunction and the increased risk of chronic kidney disease. Nonetheless, the precise role of disrupted cellular metabolism in renal injury induced by calcium oxalate (CaOx) crystal deposition is unclear. The purpose of this study is to investigate the involvement of the ubiquitin-like protein containing PHD and RING finger structural domain 1 (UHRF1) in CaOx-induced renal fibrosis and its impacts on cellular lipid metabolism.MethodsVarious approaches, including snRNA-seq, transcriptome RNA-seq, immunohistochemistry, and western blot analyses, were employed to assess UHRF1 expression in kidneys of nephrolithiasis patients, hyperoxaluric mice, and CaOx-induced renal tubular epithelial cells. Subsequently, knockdown of UHRF1 in mice and cells corroborated its effect of UHRF1 on fibrosis, ectopic lipid deposition (ELD) and fatty acid oxidation (FAO). Rescue experiments using AICAR, ND-630 and Compound-C were performed in UHRF1-knockdown cells to explore the involvement of the AMPK pathway. Then we confirmed the bridging molecule and its regulatory pathway in vitro. Experimental results were finally confirmed using AICAR and chemically modified si-UHRF1 in vivo of hyperoxaluria mice model.ResultsMechanistically, UHRF1 was found to hinder the activation of the AMPK/ACC1 pathway during CaOx-induced renal fibrosis, which was mitigated by employing AICAR, an AMPK agonist. As a nuclear protein, UHRF1 facilitates nuclear translocation of AMPK and act as a molecular link targeting the protein phosphatase PP2A to dephosphorylate AMPK and inhibit its activity.ConclusionThis study revealed that UHRF1 promotes CaOx -induced renal fibrosis by enhancing lipid accumulation and suppressing FAO via inhibiting the AMPK pathway. These findings underscore the feasible therapeutic implications of targeting UHRF1 to prevent renal fibrosis due to stones.

Project description:Renal calcium oxalate (CaOx) stone is a common urologic disease with a high prevalence and recurrence rate. However, short-chain fatty acids (SCFAs) are less often reported in the prevention of urolithiasis. This study aimed to explore the effect of SCFAs on the renal CaOx stone formation and the underlying mechanisms. Ethylene glycol was used to induce renal CaOx crystals in rats. SCFAs (acetate, propionate, or butyrate) were added as supplements to the drinking water with or without antibiotics. Because intestinal oxalate transporters SLC26A6 and SLC26A3 regulate the excretion and absorption of oxalate in the intestine, we injected adeno-associated virus 9 (AAV9)-SLC26A6-shRNA (short hairpin RNA) and AAV9-SLC26A3 into the tail vein of rats to suppress SLC26A6 and overexpress SLC26A3 expression in the intestine, respectively, to explore the role of SLC26A3 and SLC26A6 (SLC26A3/6) in the reduction of renal CaOx crystals induced by SCFAs. Results showed that SCFAs reduced renal CaOx crystals and urinary oxalate levels but, however, increased the abundance of SCFA-producing bacteria and cecum SCFA levels. SCFA supplements still reduced renal crystals and urinary oxalate after gut microbiota depletion. Propionate and butyrate downregulated intestinal oxalate transporter SLC26A3 expression, while acetate and propionate upregulated SLC26A6 expression, both in vivo and in vitro. AAV9-SLC26A3 exerted a protective effect against renal crystals, while AAV9-SLC26A6-shRNA contributed to the renal crystal formation even though the SCFAs were supplemented. In conclusion, SCFAs could reduce urinary oxalate and renal CaOx stones through the oxalate transporter SLC26A6 in the intestine. SCFAs may be new supplements for preventing the formation of renal CaOx stones. IMPORTANCE Some studies found that the relative abundances of short-chain-fatty-acid (SCFA)-producing bacteria were lower in the gut microbiota of renal stone patients than healthy controls. Our previous study demonstrated that SCFAs could reduce the formation of renal calcium oxalate (CaOx) stones, but the mechanism is still unknown. In this study, we found that SCFAs (acetate, propionate, and butyrate) reduced the formation of renal calcium oxalate (CaOx) crystals and the level of urinary oxalate. Depleting gut microbiota increased the amount of renal crystals in model rats, and SCFA supplements reduced renal crystals and urinary oxalate after gut microbiota depletion. Intestinal oxalate transporter SLC26A6 was a direct target of SCFAs. Our findings suggested that SCFAs could reduce urinary oxalate and renal CaOx stones through the oxalate transporter SLC26A6 in the intestine. SCFAs may be new supplements for preventing the formation of renal CaOx stones.

Dataset Information

Metabolomic changes in cats with renal disease and calcium oxalate uroliths.

Introduction

Objective

Method

Results

Conclusions

Publications

Metabolomic changes in cats with renal disease and calcium oxalate uroliths.

Similar Datasets

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