Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

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 BTBR Ob/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 BTBR Ob/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBR Ob/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 BTBR Ob/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumincreatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBR Ob/Wt , BTBR Ob/Ob, and hCN1 BTBR Ob/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. Jiedong Qiu, Thomas Albrecht and Shiqi Zhang contributed equally to this work. An abstract of this work has been awarded a poster prize on the congress of the German Diabetes Association (DDG) 2018 and on the International Congress on Carnosine and Anserine (ICCA) 2017 and has been presented on the congress of the European Association for the Study of Diabetes (EASD) 2018.

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“…After 2 weeks, mice were sacrificed. Carnosine concentration was measured as previously described [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…CN1 concentrations in serum ( n = 12 and 15 per group) were measured by a house-made sandwich ELISA as described previously [ 19 ]. CN1 activity was measured as previously described [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…Whether carnosine supplementation in KTRs might have beneficial effects remains to be addressed in future interventional studies. Alternatively, the use of selective CN1 inhibitors [66] or carnosine analogs resistant to CN1 activity [67] might be considered as these compounds have shown promising results in preclinical studies in diabetic models.…”

Section: Discussionmentioning

confidence: 99%

“…As anticipated, eGFR was significantly lower in KTRs (45 ± 18 mL/min/1.73 m 2 versus 92 ± 16 mL/min/1.73 m 2 ; p < 0.001). Accordingly, serum creatinine levels (125 [99-160] µmol/L versus 72 [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] µmol/L; p < 0.001) and the proportion of subjects with proteinuria (22% versus 0.5%; p < 0.001) were also significantly higher in KTRs. Additionally, systolic and diastolic blood pressures were higher in KTRs.…”

Section: Urinary Carnosine Is Reduced In Ktrs Compared To Healthy Donorsmentioning

confidence: 99%

Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study

et al. 2021

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Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4–33.3] µmol/24 h versus 34.8 [IQR 25.6–46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06–1.45]; p = 0.007). During median follow-up for 5.3 [4.5–6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44–2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted.

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“…It also improved renal function [63]. CN1 inhibitors or medications increasing internal synthesis are currently being developed [64]. In human plasma, all HDPs are present at very low concentrations, with the highest levels of homocarnosine, while the mean concentration of carnosine and ophidine/balenine was below the detection limit [65].…”

Section: Carnosine In Clinical Settingsmentioning

confidence: 99%

Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis

et al. 2020

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Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (H2S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The pathophysiological link of this crosstalk is represented by oxidative stress and inflammatory processes which contribute to the high prevalence of neuropsychiatric disorders, cognitive impairment, and dementia during the natural history of chronic kidney disease. Herein, we provide an overview of the main pathophysiological mechanisms related to high levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and neurotoxins, which play a critical role in the kidney–brain crosstalk. The present paper also explores the respective role of H2S and carnosine in the modulation of oxidative stress and inflammation in the kidney–brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.

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Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

Cited by 37 publications

References 35 publications

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

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

Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study

Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis

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