oxadiazoles and Kidney-Diseases

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

Topics: Animals; bcl-2-Associated X Protein; Benzamides; Bone Morphogenetic Protein 7; Gene Expression Regulation, Enzymologic; Hepatitis A Virus Cellular Receptor 1; Histone Deacetylase Inhibitors; Histone Deacetylases; Kidney Diseases; Lipocalin-2; Lipopolysaccharides; Male; Mice; Oxadiazoles; Proto-Oncogene Proteins c-bcl-2

Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compared with vehicle-treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination. Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy. Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys. Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen. Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus.

Topics: Animals; Disease Models, Animal; DNA; Female; Gene Expression Regulation; Immunoglobulin G; Indans; Inflammation; Kidney; Kidney Diseases; Kidney Function Tests; Lupus Erythematosus, Systemic; Mice; Oxadiazoles; Receptor, Interferon alpha-beta; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Spleen

Topics: Aminoglycosides; Codon, Nonsense; Codon, Terminator; Humans; Kidney Diseases; Oxadiazoles; Protein Biosynthesis

The effects of the ATP-sensitive potassium (KATP) channel opener YM099, and the angiotensin-converting enzyme (ACE) inhibitor captopril, on the progression of renal disease in rats with surgical renal mass reduction (RMR) were evaluated. Rats were subtotal (5/6) nephrectomized by resection of the renal poles. After 2 weeks of RMR, rats were randomized to three groups and treated for 6 weeks: no treatment (n=9); YM099 at a dose of 0.3 mg/kg by daily oral administration (n=9); or captopril at a dose of 50 mg/kg by daily oral administration (n=9). Sham-operated rats were used as normal animals (n=9). In RMR rats with no treatment, proteinuria progressively developed. At 8 weeks after RMR, renal function as assessed by plasma creatinine (Pcr) and blood urea nitrogen (BUN) was impaired. Pharmacological activation of KATP channel opening by YM099 showed no beneficial effect on proteinuria and renal functional parameters. On the other hand, pharmacological ACE inhibition by captopril significantly attenuated proteinuria, and tended to inhibit the increases in Pcr and BUN; however, these effects were not statistically significant. The presents study indicates that YM099 exhibits no renoprotection with antiproteinuric effect in rats with progressive renal disease. These findings suggest that activation of KATP channel opening may play no role in the retardation of progressive renal disease.

Topics: Animals; Captopril; Cyclic N-Oxides; Kidney Diseases; Male; Oxadiazoles; Potassium Channels; Proteinuria; Rats; Rats, Sprague-Dawley

Topics: Adult; Aged; Blood Flow Velocity; Diatrizoate; Female; Glomerular Filtration Rate; Humans; Hypertension; Hypertension, Renal; Iodine Radioisotopes; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Middle Aged; Oxadiazoles; Vasomotor System

Topics: Adult; Aged; Anti-Inflammatory Agents; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Oxadiazoles; Parasympatholytics

Topics: Adolescent; Adult; Aged; Blood Urea Nitrogen; Creatinine; Electrolytes; Female; Hemodynamics; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Oxadiazoles; Uric Acid