It has been shown that transgenic overexpression of human (pro)renin receptor (PRR) results in elevated aldosterone (Aldo) level with unclear functional implications. The present study examined a potential role of renal PRR during high K + (HK) loading. In normal SD rats, a 1-week HK intake (5% KCl in diet) induced a 3.4-fold increase in renal protein expression of full-length PRR and 4.2-fold increase in urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, at 700 μg/kg/d via i.p. injections, to K + -loaded animals elevated plasma K + level (5.72+0.08 vs. 4.84±0.18 mM, p<0.05) and decreased urinary K + excretion (2.52+0.11 vs. 3.43+0.19 mmol/24h, p<0.05), accompanied with a 26.2% reduction of urinary aldosterone (Aldo) excretion. HK downregulated NCC protein expression (57.8%) and upregulated renal protein expression of aldosterone synthase CYP11B2 (229%), ROMK (156%), calcium-activated potassium channel subunit alpha-1 (α-BK) (367%), α-Na + -K + -ATPase (596%), and β-ENaC (155%), all of which were significantly blunted by PRO20 (by 50 - 70%). The same maneuvers were applied to adrenalectomized (ADX) rats. Although plasma Aldo was extremely low and also unresponsive to HK loading, urinary Aldo excretion was elevated by 274% with this treatment, which was abolished by PRO20. The HK-induced responses of the above K + and Na + transporting proteins in ADX rats all persisted and also remained sensitive to PRO20. Additionally, spironolactone treatment in ADX rats was still effective in inhibiting kaliuresis induced by HK loading, resulting in hyperkalemia (Plasma K+: 5.13±0.07 vs. 4.19±0.27 mM, p<0.05). In primary rat IMCD cells, exposure to 10 mM KCl for 24 h augmented PRR protein expression and sPRR release in a time- and dose-dependent manner. HK upregulated Aldo release in parallel with increased CYP11B2 protein expression, which were both attenuated by PRO20 or PRR siRNA. A recombinant sPRR, sPRR-His, stimulated Aldo release and CYP11B2 expression. Taken together, we conclude that HK increased renal PRR expression that stimulates renal synthesis of Aldo that coordinates the response of renal membrane Na + and K + transporting proteins to facilitate K + secretion.
(Pro)renin receptor (PRR) is highly expressed in the distal nephron, but it has an unclear functional implication. The present study was conducted to explore a potential role of renal PRR during high K + (HK) loading. In normal Sprague-Dawley rats, a 1-wk HK intake increased renal expression of full-length PRR and urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, in K + -loaded animals elevated plasma K + level and decreased urinary K + excretion, accompanied with suppressed urinary aldosterone excretion and intrarenal aldosterone levels. HK downregulated Na + -Cl − cotransporter (NCC) expression but upregulated CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2), renal outer medullary K + channel (ROMK), calcium-activated potassium channel subunit α 1 (α-BK), α-Na + -K + -ATPase (α-NKA), and epithelial Na + channel subunit β (β-ENaC), all of which were blunted by PRO20. After HK loading was completed, urinary, but not plasma renin, was upregulated, which was blunted by PRO20. The same experiments that were performed using adrenalectomized (ADX) rats yielded similar results. Interestingly, spironolactone treatment in HK-loaded ADX rats attenuated kaliuresis but promoted natriuresis, which was associated with the suppressed responses of β-ENaC, α-NKA, ROMK, and α-BK protein expression. Taken together, we discovered a novel role of renal PRR in regulation of K + homeostasis through a local mechanism involving intrarenal renin-angiotensin-aldosterone system and coordinated regulation of membrane Na + - and K + -transporting proteins.
Review question / Objective: A number of studies have investigated the association of IL-17A rs2275913 polymorphism with susceptibility to rheumatoid arthritis (RA); however, the results remain inconsistent.We conducted this meta-analysis to investigate the relationship between IL-17A rs2275913 polymorphism and RA risk.Rationale: Recent years, the associations between six IL-17A polymorphisms and RA risk are studied by many researchers in diff e re n t p o p u l a t i o n , a n d t h e m o s t popularity variant is IL-17A (rs2275913, INPLASY
Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown. Here by using in vivo and ex vivo models, it is shown that the AP frequency per se modulates DA release through the D2 receptor (D2R), which contributes up to 50% of total DA release. D2R has a voltage-sensing site at D131 and can be deactivated in a frequency-dependent manner by membrane depolarization. This voltage-dependent D2R inhibition of DA release is mediated via the facilitation of voltage-gated Ca2+ channels (VGCCs). Collectively, this work establishes a novel mechanism that APs per se modulate DA overflow by disinhibiting the voltage-sensitive autoreceptor D2R and thus the facilitation of VGCCs, providing a pivotal pathway and insight into mammalian DA-dependent functions in vivo.
To investigate the relationship between angiotensin type I receptor (AGT I R) gene polymorphism and diabetic nephropathy (DN) and its progression.PCR technique was used to determine the AGT I R gene polymorphism in 86 patients without DN, 67 with microalbuminuria, 66 with clinical albuminuria and 20 type 2 DM patients with renal insufficiency.In comparing the DN group with the non-DN group, it was found that there was a significant difference of the frequency of AC genotype with DN (chi(2) = 4.30, P < 0.05), and C mutative type was more frequent in the DN group (chi(2) = 3.97, P < 0.05). No significant difference of AGTIR-A1166-C genotype was found in cases with different durations of DN.Delete polymorphism of A1166-C gene is associated with DN in type 2 diabetes mellitus. It is suggested that detection of significant AGTIR-A1166-C polymorphism is of help for preventing DN in type 2 diabetes mellitus.
Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by irreversible progressive cognitive deficits. Identification of candidate biomarkers, before amyloid-β-plaque deposition occurs, is therefore of great importance for early intervention of AD.To investigate the potential non-invasive early biomarkers of AD in 5XFAD mouse model, we investigate the proteome of urinary exosomes present in 1-month-old (before amyloid-β accumulation) 5XFAD mouse models and their littermate controls. Another two groups of 2 and 6 months-old urinary samples were collected for monitoring the dynamic change of target proteins during AD progression.Proteomic, bioinformatics analysis, multiple reaction monitoring (MRM), western blotting (WB) or ELISA were performed for analyzing these urinary exosomes.A total of 316 proteins including 44 brain cell markers were identified using liquid chromatography tandem mass spectrometry. Importantly, 18 proteins were unique to the 5XFAD group. Eighty-eight proteins including 11 brain cell markers were differentially expressed. Twenty-two proteins were selected to be verified by WB. Furthermore, based on an independent set of 12 urinary exosomes samples, five in these proteins were further confirmed significant difference. Notably, Annexin 2 and Clusterin displayed significant decreased in AD model during the course detected by ELISA. AOAH, Clusterin, and Ly86 are also brain cell markers that were first reported differential expression in urinary exosomes of AD model.Our data demonstrated that some urinary exosome proteins, especially Annexin 2 and Clusterin, as nanometer-sized particles, enable detection of differences before amyloid-β-plaque deposition in 5XFAD mouse model, which may present an ideal non-invasive source of biomarkers for prevention of AD.
Anxiety is a major early-onset non-motor symptom in Parkinson’s disease, but the underlying mechanisms remain largely unknown. By imaging brain circuits in an awake parkinsonian mouse model, Li, Xu et al. provide evidence that Parkinson’s disease-associated anxiety is caused by impaired postsynaptic D2 receptor-dependent dopaminergic transmission in prefrontal cortex.
Cyclooxygenase 2 (COX-2) has an established role in postnatal kidney development. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is recently identified as an endogenous inhibitor of COX-2, limiting the production of COX-2-derived prostanoids in several pathological conditions. The present study was undertaken to examine the regulation of renal 15-PGDH expression during postnatal kidney development in rats compared with COX-2. qRT-PCR and immunoblotting demonstrated that 15-PGDH mRNA and protein in the kidney were present in neonates, peaked in the second postnatal week, and then declined sharply to very low level in adulthood. Immunostaining demonstrated that at the second postnatal week, renal 15-PGDH protein was predominantly found in the proximal tubules stained positive for Na/H exchanger 3 and brush borders (periodic acid-Schiff), whereas COX-2 protein was restricted to macular densa and adjacent thick ascending limbs. Interestingly, in the fourth postnatal week, 15-PGDH protein was redistributed to thick ascending limbs stained positive for the Na-K-2Cl cotransporter. After 6 wk of age, 15-PGDH protein was found in the granules in subsets of the proximal tubules. Overall, these results support a possibility that 15-PGDH may regulate postnatal kidney development through interaction with COX-2.
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