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Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice.

ABSTRACT: OBJECTIVE:To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). METHODS:hCN1 transgenic (TG) mice were generated in a BTBROb/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBROb/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBROb/Ob mice. RESULTS:hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBROb/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumin-creatinine ratios (1104 ± 696 vs 492.1 ± 282.2 ?g/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBROb/Wt, BTBROb/Ob, and hCN1 BTBROb/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator-activated receptor-alpha have been reported to play essential roles in DKD. CONCLUSIONS:Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. KEY MESSAGES:Increased carnosinase 1 (CN1) is associated with diabetic kidney disease (DKD). BTBROb/Ob mice with human CN1 develop a more aggravated DKD phenotype. Microarray revealed alterations by CN1 which are not altered by hyperglycemia. These genes have been described to play essential roles in DKD. Inhibiting CN1 could be beneficial in DKD.

SUBMITTER: Qiu J

PROVIDER: S-EPMC7447680 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBR<sup>Ob/Ob</sup> mice.

Qiu Jiedong J Albrecht Thomas T Zhang Shiqi S Hauske Sibylle J SJ Rodriguez-Niño Angelica A Zhang Xinmiao X Nosan Darya D Pastene Diego O DO Sticht Carsten C Delatorre Carolina C van Goor Harry H Porubsky Stefan S Krämer Bernhard K BK Yard Benito A BA

Journal of molecular medicine (Berlin, Germany) 20200815 9

<h4>Objective</h4>To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD).<h4>Methods</h4>hCN1 transgenic (TG) mice were generated in a BTBR<sup>Ob/Ob</sup> genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBR<sup>Ob/Ob</sup> mice leads to cha ...[more]

PMID: 32803273

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Project description:ObjectiveObesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis.MethodsSepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis.ResultsWe observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65.ConclusionSIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.

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Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice.

Publications

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBR<sup>Ob/Ob</sup> mice.

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