neuropeptide-y and Diabetic-Nephropathies

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that

Topics: Albuminuria; Animals; Arginine; Benzazepines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Down-Regulation; Doxorubicin; Humans; Insulin; Kidney Diseases; Kidney Glomerulus; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neuropeptide Y; Podocytes; Proteomics; Receptors, Neuropeptide Y; Signal Transduction

Diabetic retinopathy (DR) is one of the major complications of diabetes, which eventually leads to blindness. Up to date, no animal model has yet shown all the co-morbidities often observed in DR patients. Here, we investigated whether obese 42 weeks old ZSF1 rat, which spontaneously develops diabetes, hypertension and obesity, would be a suitable model to study DR. Although arteriolar tortuosity increased in retinas from obese as compared to lean (hypertensive only) ZSF1 rats, vascular density pericyte coverage, microglia number, vascular morphology and retinal thickness were not affected by diabetes. These results show that, despite high glucose levels, obese ZSF1 rats did not develop DR. Such observations prompted us to investigate whether the expression of genes, possibly able to contain DR development, was affected. Accordingly, mRNA sequencing analysis showed that genes (i.e. Npy and crystallins), known to have a protective role, were upregulated in retinas from obese ZSF1 rats. Lack of retina damage, despite obesity, hypertension and diabetes, makes the 42 weeks of age ZSF1 rats a suitable animal model to identify genes with a protective function in DR. Further characterisation of the identified genes and downstream pathways could provide more therapeutic targets for the treat DR.

Topics: Animals; Blood Glucose; Crystallins; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diabetic Retinopathy; Disease Models, Animal; Gene Expression Profiling; Hypertension; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Rats; Retina

Dipeptidyl peptidase IV converts neuropeptide Y(1-36) (Y(1)-receptor agonist released from renal sympathetic nerves) to neuropeptide Y(3-36) (selective Y(2)-receptor agonist). Previous studies suggest that Y(1), but not Y(2), receptors enhance renovascular responses to angiotensin II in kidneys from genetically-susceptible animals. Therefore, we hypothesized that inhibition of dipeptidyl peptidase IV with sitagliptin (antidiabetic drug) would augment the ability of exogenous and endogenous neuropeptide Y(1-36) to enhance renal vascular responses to angiotensin II in kidneys from spontaneously hypertensive rats. This hypothesis was tested using 3 protocols in isolated perfused kidneys. Results from Protocol 1: Exogenous neuropeptide Y(1-36) enhanced renovascular responses to angiotensin II. This effect of neuropeptide Y(1-36) was blocked by BIBP3226 (selective Y(1) receptor antagonist); Exogenous neuropeptide Y(3-36) did not enhance renovascular responses to angiotensin II. Results from Protocol 2: Sitagliptin augmented the ability of exogenous neuropeptide Y(1-36) to enhance renovascular responses to angiotensin II. This effect of sitagliptin was blocked by BIBP3226. Results from Protocol 3: Renal sympathetic nerve stimulation enhanced renovascular responses to angiotensin II; this enhancement was augmented by sitagliptin and abolished by BIBP3226. Neuropeptide Y(1-36) via Y(1) receptors enhances renovascular responses to angiotensin II in kidneys from genetically hypertensive animals. Sitagliptin, by blocking dipeptidyl peptidase IV, prevents metabolism of neuropeptide Y(1-36) and thereby increases the effects of neuropeptide Y(1-36) released from renal sympathetic nerves on Y(1) receptors leading to augmentation of neuropeptide Y(1-36)-induced enhancement of the renovascular effects of angiotensin II. The renal effects of dipeptidyl peptidase IV inhibitors in hypertensive diabetic patients merit a closer examination.

Topics: Angiotensin II; Animals; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Synergism; Hypertension, Renal; Kidney; Male; Neuropeptide Y; Peptide Fragments; Pyrazines; Rats; Rats, Inbred SHR; Renal Circulation; Sitagliptin Phosphate; Sympathetic Nervous System; Triazoles; Vasoconstrictor Agents

The distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations.. One sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study.. Genotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization.. The C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249-5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD.. The present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leucine; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Proline; Sweden; United States

Several studies have shown genetic predisposition for diabetic complications. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY has been shown to be a risk factor for diabetic retinopathy in type 1 diabetes. In the current study we examined the contribution of this polymorphism on the progression of retinopathy in Caucasian type 1 and type 2 diabetes patients. Patients with type 2 diabetes and the Leu7Pro polymorphism developed retinopathy at younger age because of markedly earlier disease onset of diabetes (RC- 6.8, 95% CI-12.2 - [- 1.5]), but no association of the Leu7Pro polymorphism with the current severity of retinopathy was detected. A strong association of the polymorphism with proteinuria in type 2 diabetes patients with retinopathy could be detected (OR 3.1, 95% CI 1.1-8.8); 31% of subjects having both retinopathy and proteinuria had the polymorphism compared to only 13% of retinopathy patents without concomitant proteinuria (p = 0.032). Plasma concentrations of NPY were increased in subjects with proteinuria (79.2+/-28.4 and 64.7+/-26.2 pmol/l, p = 0.001). These results suggest that the Leu7Pro polymorphism could be used to predict earlier onset of type 2 diabetes and retinopathy, and increased risk for diabetic nephropathy.

Topics: Adult; Age Factors; Aged; Amino Acid Substitution; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Predictive Value of Tests; Protein Precursors; Proteinuria; Retrospective Studies; Risk Factors; White People

Neuropeptide Y (NPY) is a potent vasoconstrictor peptide that is abundant in the brain and the peripheral sympathetic nervous system. In the present study we investigated possible changes in plasma immunoreactive (IR)-NPY concentrations and urinary IR-NPY excretion in patients with non-insulin dependent diabetes mellitus (NIDDM) and the relationship to diabetic complications, such as nephropathy and neuropathy. IR-NPY in plasma and urine was measured by radioimmunoassay in 69 patients with NIDDM. Plasma IR-NPY concentrations in patients with advanced nephropathy (creatinine clearance <30 ml/min) (100.5 +/- 10.3 pmol/l, n=9, mean +/- SEM) were higher than in the control subjects (55.0 +/- 6.8 pmol/l, n=15) (P<0.02). Urinary excretion of IR-NPY and fractional excretion of NPY were also increased in the patients with advanced nephropathy. Sephadex G-50 column chromatography of the urine extracts obtained from healthy subjects, diabetic patients with renal failure and non-diabetic patients with renal failure showed an immunoreactive peak eluting in the NPY position. On the other hand, neither plasma nor urinary IR-NPY was high in patients with retinopathy, or in patients with peripheral neuropathy. The present study has, for the first time, shown high plasma IR-NPY concentrations and urinary IR-NPY excretion in NIDDM patients with advanced nephropathy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Neuropeptide Y; Reference Values