sitagliptin-phosphate and Proteinuria

This study investigated the molecular mechanisms underlying the antiproteinuric effect of DPP4 inhibition in 5/6 renal ablation rats and tested the hypothesis that the urinary activity of DPP4 correlates with chronic kidney disease (CKD) progression. Experiments were conducted in male Wistar rats who underwent 5/6 nephrectomy (Nx) or sham operation followed by 8 wk of treatment with the DPP4 inhibitor (DPP4i) sitagliptin or vehicle. Proteinuria increased progressively in Nx rats throughout the observation period. This increase was remarkably mitigated by sitagliptin. Higher levels of proteinuria in Nx rats compared to control rats were accompanied by higher urinary excretion of retinol-binding protein 4, a marker of tubular proteinuria, as well as higher urinary levels of podocin, a marker of glomerular proteinuria. Retinol-binding protein 4 and podocin were not detected in the urine of Nx + DPP4i rats. Tubular and glomerular proteinuria was associated with the reduced expression of megalin and podocin in the renal cortex of Nx rats. Sitagliptin treatment partially prevented this decrease. Besides, the angiotensin II renal content was significantly reduced in the Nx rats that received sitagliptin compared to vehicle-treated Nx rats. Interestingly, both urinary DPP4 activity and abundance increased progressively in Nx rats. Additionally, urinary DPP4 activity correlated positively with serum creatinine levels, proteinuria, and blood pressure. Collectively, these results suggest that DPP4 inhibition ameliorated both tubular and glomerular proteinuria and prevented the reduction of megalin and podocin expression in CKD rats. Furthermore, these findings suggest that urinary DPP4 activity may serve as a biomarker of renal disease and progression.

Topics: Angiotensin II; Animals; Biomarkers; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Fibrosis; Intracellular Signaling Peptides and Proteins; Kidney; Low Density Lipoprotein Receptor-Related Protein-2; Male; Membrane Proteins; Proteinuria; Rats, Wistar; Renal Insufficiency, Chronic; Retinol-Binding Proteins, Plasma; Signal Transduction; Sitagliptin Phosphate

Diabetic nephropathy (DN) is a common cause of end-stage kidney disease (ESKD) all over the world. Sitagliptin, an inhibitor of DPP-IV plays a beneficial role in type 2 diabetic nephropathy. The purpose of this study was to explore the effect and mechanism of sitagliptin on renal injury in type 1 diabetic mice. Streptozotocin (STZ) induced type 1 diabetic mice were treated with oral administration of sitagliptin (15 mg/kg/ day) for 4 weeks. The results showed that sitagliptin treatment did not change the levels of blood glucose in STZ induced type 1 diabetic mice. Sitagliptin attenuates diabetic nephropathy by significantly inhibiting 24 h proteinuria, renal injury and fibrosis. Sitagliptin can inhibit the expression level of TGF-β1 and the other related fibrosis factors in renal tissue of type 1 diabetic mice while delaying the progression of type 1 diabetic nephropathy. These results indicated that sitagliptin treatment is potentially a new strategy for treating type 1 diabetic nephropathy.

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Male; Mice; Proteinuria; Signal Transduction; Sitagliptin Phosphate; Smad Proteins; Streptozocin; Transforming Growth Factor beta1

This study aimed to investigate the potential protective effect of sitagliptin on gentamicin-induced nephrotoxicity and to elucidate the underlying mechanism.. Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and. received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase-3 and bax were evaluated.. Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase-3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment.. These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Blood Glucose; Blood Urea Nitrogen; Creatinine; Cytoprotection; Disease Models, Animal; Electron Transport; Energy Metabolism; Gentamicins; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Mitochondria; Oxidative Stress; Proteinuria; Rats, Wistar; Sitagliptin Phosphate

This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.. Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 μm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4).. Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-α, IL-1β, PAI-1), protein (TNF-α, NF-κB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).. Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

Topics: Animals; Biomarkers; Creatinine; Exenatide; Inflammation; Kidney; Male; Oxidative Stress; Peptides; Proteinuria; Pyrazines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Sitagliptin Phosphate; Triazoles; Venoms

1. Dipeptidyl peptidase (DPP) IV inhibitors enhance renovascular responses to angiotensin (Ang) II in spontaneously hypertensive rats (SHR), but not Wistar-Kyoto rats. Because DPPIV inhibitors are often used in metabolic syndrome, it is important to determine whether DPPIV inhibition in this setting enhances renovascular responses to AngII. 2. Six-week-old Lean-ZSF1 rats (harbouring SHR genes, but without metabolic syndrome; n = 11) and Obese-ZSF1 rats (harbouring SHR genes and expressing metabolic syndrome; n = 10) were provided food and water ad libitum, and metabolic parameters and renovascular responses to AngII were assessed when the animals were 7 and 8 weeks of age, respectively. 3. At 7 weeks of age, compared with Lean-ZSF1, Obese-ZSF1 demonstrated significant (P < 0.05) increases in bodyweight (262 +/- 8 vs 310 +/- 13 g), plasma glucose (112 +/- 4 vs 153 +/- 9 mg/dL), haemoglobin A1c (4.7 +/- 0.1 vs 5.8 +/- 0.4%), urinary glucose excretion (0.021 +/- 0.003 vs 6.70 +/- 1.80 g/kg bodyweight per 24 h) and urinary protein excretion (100 +/- 7 vs 313 +/- 77 mg/kg bodyweight per 24 h). Mean blood pressure was high (133 +/- 7 mmHg) in both strains. 4. At 8 weeks of age, kidneys were isolated and perfused. In Lean-ZSF1 rats, renovascular responses (i.e. changes in perfusion pressure) to physiological levels of AngII (0.1 nmol/L) were 3.4 +/- 1.3 and 18.2 +/- 5.9 mmHg in untreated (n = 5) and 1 micromol/L sitagliptin-treated (n = 6) kidneys, respectively. In Obese-ZSF1 rats, renovascular responses to AngII were 5.5 +/- 1.3 and 17.8 +/- 8.2 mmHg in untreated (n = 4) and sitagliptin-treated (n = 6) kidneys, respectively. Analysis of variance revealed a significant (P = 0.0367) effect of sitagliptin on renovascular responses to AngII that was independent of strain. 5. In conclusion, sitagliptin enhances renovascular responses to AngII in rats harbouring SHR genes and this effect persists in rats with diabetic nephropathy and metabolic syndrome.

Topics: Angiotensin II; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Hypertension; Kidney; Male; Metabolic Syndrome; Proteinuria; Pyrazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Sitagliptin Phosphate; Triazoles; Vasoconstriction; Vasoconstrictor Agents