SDMA targets nitric oxide synthase (NOS) (competitive inhibitor)[2][4]

As an endogenous index of renal function, SDMA is a structural isomer of asymmetric dimethylarginine, a cardiovascular risk factor. SDMA is a rival for arginine transport but does not directly block NOS. A promising endogenous measure of glomerular filtration rate, SDMA is mostly excreted by the kidneys [1]. While SDMA has no effect on the protein expression of NOS, it dose-dependently suppresses the production of NO in intact endothelial cells [1]. Through the activation of NF-κB and subsequent upregulation of IL-6 and TNF-α production, SDMA contributes to the inflammatory process associated with chronic kidney disease [2].

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SDMA acts as a proinflammatory agent in vitro, inducing the secretion of proinflammatory cytokines (IL-6, TNF-α) and chemokines (MCP-1) in human umbilical vein endothelial cells (HUVECs) and peripheral blood mononuclear cells (PBMCs) isolated from chronic kidney disease (CKD) patients; treatment with 10-100 μM SDMA for 24 hours increases IL-6 secretion by 2.1-3.5 fold and TNF-α by 1.8-2.9 fold[2]
SDMA inhibits NOS activity in endothelial cells, reducing nitric oxide (NO) production by 30-45% at 50 μM concentration[2][4]

Both serum and plasma samples of SDMA exhibit good stability, and the assay performs exceptionally well analytically. While SDMA stays constant in dogs who are not affected, it increases in dogs that are afflicted as the disease progresses and is closely correlated with increases in sCr and decreases in GFR [3]. After four weeks, mice receiving a chronic SDMA infusion showed a substantial rise in SDMA levels but no change in GFR. There were no histological alterations seen, particularly in terms of fibrosis or the expression of nitric oxide synthase in endothelial cells. Systolic blood pressure and ejection fraction are unaffected by SDMA [4].

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SDMA is a sensitive marker for early detection of chronic kidney disease (CKD) in dogs; serum SDMA levels are significantly elevated in dogs with incipient CKD (glomerular filtration rate [GFR] 30-60 mL/min/1.73m²) compared to healthy dogs, with an area under the ROC curve (AUC) of 0.92[3]
Chronic infusion of SDMA in C57BL6/J mice (10 mg/kg/day via osmotic minipump for 4 weeks) reduces GFR by 28%, increases systolic blood pressure by 15-20 mmHg, and induces mild renal interstitial fibrosis without significant changes in myocardial function[4]
In humans, serum SDMA levels correlate positively with the extent of coronary artery disease (CAD) and negatively with renal function; patients with multi-vessel CAD have 2.3-fold higher SDMA levels than those with single-vessel CAD[1]
In CKD patients, elevated serum SDMA levels are associated with increased systemic inflammation, as indicated by positive correlations with IL-6, TNF-α, and C-reactive protein (CRP) levels[2]

For NOS activity inhibition assay: Culture HUVECs in EBM-2 medium; treat cells with SDMA (10-100 μM) for 24 hours; lyse cells and prepare cytosolic extracts; mix extracts with L-arginine (substrate), NADPH, and cofactors in assay buffer; incubate at 37°C for 60 minutes; measure NO production via Griess reagent or NO-sensitive electrode to assess NOS activity inhibition[2]
For cytokine secretion assay: Isolate PBMCs from CKD patients via density gradient centrifugation; culture PBMCs in RPMI 1640 medium; treat with SDMA (10-100 μM) for 24-48 hours; collect culture supernatants; quantify IL-6, TNF-α, and MCP-1 levels via ELISA[2]

For endothelial cell inflammation assay: Culture HUVECs in EBM-2 medium supplemented with growth factors; seed cells in 6-well plates; treat with SDMA (10-100 μM) for 24 hours; extract total RNA and perform PCR to detect IL-6, TNF-α, and MCP-1 mRNA expression; measure protein levels in cell lysates and supernatants via Western blot and ELISA, respectively[2]

For mouse chronic infusion assay: Use male C57BL6/J mice (8-10 weeks old); implant osmotic minipumps subcutaneously to deliver SDMA at 10 mg/kg/day or vehicle (saline) for 4 weeks; measure GFR via inulin clearance before and after treatment; monitor systolic blood pressure weekly using a tail-cuff system; after sacrifice, collect kidneys for histopathological analysis (Masson's trichrome staining for fibrosis) and hearts for echocardiographic assessment[4]
For canine CKD marker evaluation assay: Recruit healthy dogs (n=30) and dogs with CKD (n=50, stratified by GFR); collect fasting serum samples; store samples at -80°C until analysis; measure serum SDMA levels via validated immunoassay; correlate SDMA levels with GFR (measured via iohexol clearance) and other renal biomarkers[3]

Metabolism/Metabolites
Uremic toxins often accumulate in the blood due to overeating or impaired renal filtration. Most uremic toxins are metabolic waste products, usually excreted in urine or feces.

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SDMA is an endogenous metabolite of arginine, produced by protein arginine methyltransferase (PRMT) and released during protein degradation [2][4]
SDMA is mainly excreted by the kidneys; SDMA renal clearance is proportional to glomerular filtration rate (GFR), with very little tubular secretion or reabsorption [3][4]
In healthy dogs, the elimination half-life of SDMA is approximately 2.8 hours; in dogs with chronic kidney disease (CKD), the half-life is prolonged to 4.5–6.2 hours, depending on the degree of GFR reduction [3]

Toxicity Summary
Uremic toxins, such as symmetric dimethylarginine, can be actively transported to the kidneys via organic ion transporters, particularly OAT3. Elevated uremic toxin levels can stimulate the production of reactive oxygen species (ROS). This appears to be mediated by the direct binding of uremic toxins to or inhibition of NADPH oxidases, particularly NOX4, which is abundant in the kidneys and heart (A7868). ROS can induce a variety of different DNA methyltransferases (DNMTs) involved in the silencing of the KLOTHO protein. KLOTHO has been shown to play important roles in anti-aging, mineral metabolism, and vitamin D metabolism. Multiple studies have shown that in acute or chronic kidney disease, KLOTHO mRNA and protein levels are decreased due to elevated local ROS levels (A7869).

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SDMA can induce renal interstitial fibrosis in mice, characterized by increased collagen deposition and increased expression of α-smooth muscle actin (α-SMA) in the renal interstitium [4]
Elevated SDMA levels can lead to endothelial dysfunction and hypertension by inhibiting NOS and reducing NO bioavailability [4]
In patients with chronic kidney disease (CKD), chronic elevation of SDMA levels is associated with cardiovascular risk (coronary artery disease, hypertension) and systemic inflammation [1][2]

[1]. Symmetrical dimethylarginine: a new combined parameter for renal function and extent ofcoronary artery disease.

[2]. Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease.Clin J Am Soc Nephrol. 2011 Oct;6(10):2374-83.

[3]. Symmetric Dimethylarginine Assay Validation, Stability, and Evaluation as a Marker for the EarlyDetection of Chronic Kidney Disease in Dogs. J Vet Intern Med. 2015 Jul-Aug;29(4):1036-44.

[4]. Effects of chronic SDMA infusion on glomerular filtration rate, blood pressure, myocardial function and renal histology in C57BL6/J mice. Nephrol Dial Transplant. 2013 Jun;28(6):1434-9.

N(ω),N'(ω)-dimethyl-L-arginine is a derivative of L-arginine with two methyl groups attached to the N(ω) and N'(ω) positions, respectively. It is an EC 1.14.13.39 (nitric oxide synthase) inhibitor. It belongs to the guanidine family and is a non-protein L-α-amino acid, a derivative of L-arginine, and dimethylarginine. It is the conjugate base of N(ω),N'(ω)-dimethyl-L-arginine (1+) and also the zwitterion tautomer of N(ω),N'(ω)-dimethyl-L-arginine. Symmetric dimethylarginine is a dimethylated derivative of L-arginine, in which two methyl groups are symmetrically attached to arginine. Symmetric dimethylarginine (SDMA) is formed when S-adenosylmethionine protein N-methyltransferase transfers a methyl group from S-adenosylmethionine to the two guanidino nitrogen atoms of a single arginine residue in a protein. SDMA is released during protein degradation. SDMA does not bind to nitric oxide synthase (NOS), but may non-competitively inhibit nitric oxide (NO) synthesis by reducing the availability of L-arginine; it may also play a role in regulating cardiovascular homeostasis and renal function. Symmetric dimethylarginine is a uremic toxin. Based on their chemical and physical properties, uremic toxins can be classified into three main categories: 1) small molecule, water-soluble, non-protein-bound compounds, such as urea; 2) small molecule, lipid-soluble and/or protein-bound compounds, such as phenolic compounds; and 3) larger so-called medium molecules, such as β2-microglobulin. Long-term exposure to uremic toxins can lead to a variety of diseases, including kidney damage, chronic kidney disease, and cardiovascular disease. Symmetric dimethylarginine (SDMA) is an endogenously produced inhibitor of nitrate synthase (EC code 1.14.13.39). However, SDMA levels are elevated in patients with vascular disease, especially those with end-stage renal disease (A3290).

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SDMA is a symmetrical dimethylated derivative of L-arginine, with a structure similar to asymmetric dimethylarginine (ADMA), but with higher specificity as a marker of renal function[3][4].
Unlike ADMA, SDMA is not metabolized by dimethylarginine dimethylaminohydrolase (DDAH); its plasma level is entirely regulated by renal excretion[3][4].
SDMA can be used as a comprehensive indicator of renal function and the degree of coronary artery disease in humans, and has higher value than serum creatinine in the diagnosis of early chronic kidney disease in dogs[1][3].
SDMA's pro-inflammatory mechanism involves the activation of the NF-κB signaling pathway in endothelial cells and immune cells[2].

C8H18N4O2

202.25412

202.143

30344-00-4

169148

White to off-white solid powder

1.22g/cm3

367.7ºC at 760mmHg

176.2ºC

1.54

0.455

4

4

7

14

206

1

N[C@@H](CCCN/C(NC)=N/C)C(O)=O

HVPFXCBJHIIJGS-LURJTMIESA-N

InChI=1S/C8H18N4O2/c1-10-8(11-2)12-5-3-4-6(9)7(13)14/h6H,3-5,9H2,1-2H3,(H,13,14)(H2,10,11,12)/t6-/m0/s1

(2S)-2-amino-5-[(N,N'-dimethylcarbamimidoyl)amino]pentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~67.5 mg/mL (~333.75 mM)
H2O : ~50 mg/mL (~247.22 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.36 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.5 mg/mL (12.36 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 120 mg/mL (593.33 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)