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In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.
Copyright © 2015 by the American Society of Nephrology.
Disrupted dopamine (DA) signaling is believed to contribute to the core features of multiple neuropsychiatric and neurodegenerative disorders. Essential features of DA neurotransmission are conserved in the nematode Caenorhabditis elegans, providing us with an opportunity to implement forward genetic approaches that may reveal novel, in vivo regulators of DA signaling. Previously, we identified a robust phenotype, termed Swimming-induced paralysis (Swip), that emerges in animals deficient in the plasma membrane DA transporter. Here, we report the use and quantitative analysis of Swip in the identification of mutant genes that control DA signaling. Two lines captured in our screen (vt21 and vt22) bear novel dat-1 alleles that disrupt expression and surface trafficking of transporter proteins in vitro and in vivo. Two additional lines, vt25 and vt29, lack transporter mutations but exhibit genetic, biochemical, and behavioral phenotypes consistent with distinct perturbations of DA signaling. Our studies validate the utility of the Swip screen, demonstrate the functional relevance of DA transporter structural elements, and reveal novel genomic loci that encode regulators of DA signaling.
Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Randomized clinical trials have clearly shown that inhibition of the renin-angiotensin system (RAS) will slow the rate of progression of diabetic nephropathy, but controversy remains about whether the observed beneficial effects result from more than control of blood pressure. Deletion of eNOS in a model of type II diabetes, db/db mice (eNOS(-/-) db/db), induces an accelerated nephropathy and provides an excellent model of human diabetic nephropathy. As is frequently seen in type II diabetes, blood pressure is moderately elevated in eNOS(-/-) db/db mice. To determine the role of elevated blood pressure per se vs. additional deleterious effects of the RAS in mediation of disease progression, 8-wk-old eNOS(-/-) db/db mice were randomly divided into three groups: vehicle, treatment with the angiotensin-converting enzyme inhibitor (ACEI) captopril, or treatment with "triple therapy" (hydralazine, resperine, hydrocholorothiazide), and the animals were euthanized after treatment for 12 wk. Blood pressure was reduced to comparable levels with ACE inhibition or triple therapy. Although both treatment regimens decreased development of diabetic nephropathy, ACE inhibition led to more profound reductions in albuminuria, glomerulosclerosis, markers of tubulointerstitial injury, macrophage infiltration, and markers of inflammation. Therefore, this animal model suggests that while there is an important role for blood pressure control, RAS blockade provides additional benefits in slowing the progression of diabetic nephropathy.
Dopamine is essential to the proper functioning of basal ganglia (BG) because loss of dopaminergic input profoundly alters the activity of these nuclei. Experimental evidence suggests that multiple aspects of glutamatergic neurotransmission in the BG are altered with the loss of dopaminergic input. Using whole-cell patch-clamp recording in rat brain slices, we examined whether activity of dopamine receptors is necessary to maintain signaling properties of group I metabotropic glutamate receptor subtypes, mGluR1 and 5, in the rat globus pallidus (GP), one of the nuclei in the BG circuit. Dopaminergic depletion due to systemic treatment with reserpine caused a change in the signaling properties of group I mGluRs, where mGluR1 lost the ability to depolarize GP neurons, while mGluR5 gained such ability. Bath-application of dopamine or D1- and D2-like dopamine receptor agonists to slices from reserpinized rats partly reversed these effects and caused mGluR1 to gain back its ability to depolarize GP neurons. On the other hand, stimulation of either D1-like or D2-like dopamine receptors was sufficient to abolish the activating properties of mGluR5 acquired following reserpine treatment. Interestingly, inhibition of protein kinase A activity alone was sufficient to largely reverse plasticity in function of group I mGluRs that was induced by reserpine treatment. Our data reveal that specific roles of group I mGluRs in the GP depend on the activity of D1-like and D2-like dopamine receptors, further corroborating the importance of dopamine in maintaining proper glutamatergic neurotransmission in the BG.
The globus pallidus (GP) is a key GABAergic nucleus in the basal ganglia (BG). The predominant input to the GP is an inhibitory striatal projection that forms the first synapse in the indirect pathway. The GP GABAergic neurons project to the subthalamic nucleus, providing an inhibitory control of these glutamatergic cells. Given its place within the BG circuit, it is not surprising that alterations in GP firing pattern are postulated to play a role in both normal and pathological motor behavior. Because the inhibitory striatal input to the GP may play an important role in shaping these firing patterns, we set out to determine the role that the group III metabotropic glutamate receptors (GluRs) play in modulating transmission at the striatopallidal synapse. In rat midbrain slices, electrical stimulation of the striatum evoked GABA(A)-mediated IPSCs recorded in all three types of GP neurons. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited these IPSCs through a presynaptic mechanism of action. L-AP4 exhibited high potency and a pharmacological profile consistent with mediation by mGluR4. Furthermore, the effect of L-AP4 on striatopallidal transmission was absent in mGluR4 knock-out mice, providing convincing evidence that mGluR4 mediates this effect. The finding that mGluR4 may selectively modulate striatopallidal transmission raises the interesting possibility that activation of mGluR4 could decrease the excessive inhibition of the GP that has been postulated to occur in Parkinson's disease. Consistent with this, we find that intracerebroventricular injections of L-AP4 produce therapeutic benefit in both acute and chronic rodent models of Parkinson's disease.
A history of peptic ulcer disease is frequently cited as a contraindication to the use of reserpine. However, the risk of ulcer disease associated with the use of reserpine at current therapeutic doses is unknown. To address this question, the authors conducted a nested case-control study of the association between reserpine use and hospitalizations for peptic ulcer disease in elderly Tennessee Medicaid enrollees. When compared with that of nonusers of reserpine, the relative risk of hospitalization for peptic ulcer disease was 0.8 (95% CI, 0.6-1.0) among current users and 0.8 (95% CI, 0.5-1.3) among former users. The authors' data provide evidence that reserpine is not associated with ulcer disease in elderly persons and suggest that a history of ulcer disease need not be a contraindication to the use of this drug.
A retrospective chart analysis was conducted on all new elderly hypertensive patients referred to a community hypertension clinic who were being treated with either reserpine or alpha-methyldopa plus a diuretic. There were no significant differences between the two groups on entry in age, gender, co-morbid diagnoses, or systolic or diastolic blood pressure. There were no significant differences between the two groups in terms of side effects over three years, but the proportion of persons having compliance problems was significantly lower in the reserpine group. Mean diastolic pressures were significantly lower after one, two, and three years, and systolic pressures were lower after one and two years in the reserpine group. Reserpine is at least as effective as alpha-methyldopa in treating hypertension in the elderly and is associated with fewer problems in compliance.
Systemic fencamfamine (0.5-16 mg/kg, i.v.) significantly but incompletely inhibited spontaneous activity of nigrostriatal and mesolimbic/mesocortical dopamine (DA) neurons. Inhibition was reversed by haloperidol (0.1 mg/kg, i.v.) and prevented by pretreatment with alpha-methyltyrosine (50 mg/kg, i.v.) plus reserpine (5 mg/kg, i.p.). Pretreatment with alpha-methyltyrosine alone attenuated inhibition at high but not low doses of fencamfamine. Microiontophoresed fencamfamine had little direct effect on DA neurons and did not consistently modulate the effects of co-microiontophoresed DA. In contrast, systemic fencamfamine blocked the inhibitory effects of low doses of apomorphine (10-40 micrograms/kg, i.v.). Fencamfamine appears to be an indirect DA agonist which interacts with both vesicular and newly synthesized DA storage pools. Fencamfamine may also cause a rapid desensitization to the effects of DA autoreceptor stimulation.