Alteration in kidney glucose and amino acids are implicated in renal pathology in MRL/lpr mice.
This study has employed high-resolution NMR spectroscopy of kidney extracts to study alterations in the concentrations of amino acids and glucose in systemic lupus erythematosus (SLE). We used the well-established mouse model of SLE, MRL/lpr, and their congenic controls, MRL/+. There was a substantial increase in the tissue concentration of branched-chain amino acids (133%), aromatic amino acids (134%) and glutathione (122%) in the lupus mice, compared to the controls. Since increased glucose can lead to fibrosis, we used [1-(13)C] glucose as a tracer to study its transport into the kidney. Significant increases in the levels of [1-(13)C] glucose (200% of controls) were observed in the MRL/lpr mice 15 min after its injection. 13C NMR spectra demonstrated that the 13C-label from [1-(13)C] glucose was not incorporated into glycolytic and Krebs cycle related metabolites within 15 min. Furthermore, we found that the expression of the profibrotic cytokine, TGFbeta and the regulatory transcription factor Smad3 are significantly enhanced in MRL/lpr mice compared to the MRL/+ controls. The mRNA and protein expression of extracellular matrix proteins, fibronectin, laminin, and collagen IV were upregulated in the MRL/lpr mice compared to the controls. All these changes were significantly reduced by the complement (C) inhibitor, Crry. Our results suggest that C activation causes increased glucose concentration in the kidney, which can lead to the observed hyperglycemia. This may be one of the important factors that cause increased extracellular matrix (ECM) deposition through the TGFbeta signaling in lupus mice and thereby lead to glomerulosclerosis that translates into increased kidney disease.
Alexander
Jessy J
JJ
Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
Zwingmann
Claudia
C
Jacob
Alexander
A
Quigg
Richard
R
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002097:C-Reactive Protein / Q000096:biosynthesis; D002952:Citric Acid Cycle; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005355:Fibrosis; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011951:Receptors, Complement / Q000096:biosynthesis; D017463:Receptors, Complement 3b; D051900:Smad3 Protein / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
D000596:Amino Acids; C081470:Cr1l protein, mouse; D016326:Extracellular Matrix Proteins; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D002097:C-Reactive Protein; D005947:Glucose