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Altered expression profile of renal ?(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists.

ABSTRACT: Alpha(1D)-adrenergic receptor (?(1D)-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile of ?(1D)-AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosiglitazone for 8-10 weeks. Gene microarray, real-time PCR, and confocal immunofluorescence microscopy were performed to assess mRNA and protein expression of ?(1D)-AR in rat kidney tissue. Using microarray, we found that ?(1D)-AR gene was dramatically upregulated in 22-week-old ZD rats compared to ZL controls. Quantitative PCR analysis verified a 16-fold increase in ?(1D)-AR mRNA in renal cortex from ZD animals compared to normal controls. Chronic treatment with fenofibrate or rosiglitazone reduced renal cortical ?(1D)-AR gene. Immunofluorescence staining confirmed that ?(1D)-AR protein was induced in the glomeruli and tubules of diabetic rats. Moreover, dual immunostaining for ?(1D)-AR and kidney injury molecule-1 indicated that ?(1D)-AR was expressed in dedifferentiated proximal tubules of diabetic Zucker rats. Taken together, our results show that ?(1D)-AR expression is upregulated in the diabetic kidneys. PPAR activation suppressed renal expression of ?(1D)-AR in diabetic nephropathy.

SUBMITTER: Zhao X

PROVIDER: S-EPMC3977090 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Altered expression profile of renal α(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists.

Zhao Xueying X Zhang Yuanyuan Y Leander Michelle M Li Lingyun L Wang Guoshen G Emmett Nerimiah N

Journal of diabetes research 20140317

Alpha(1D)-adrenergic receptor (α(1D)-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile of α(1D)-AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosigl ...[more]

PMID: 24772448

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Project description:Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.

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Altered expression profile of renal ?(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists.

Publications

Altered expression profile of renal α(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists.

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