yasamy R, Raghavaraju G, Pandey KN. Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice.
The objective of the present study was to delineate the mechanisms of GC-A/natriuretic peptide receptor-A (GC-A/ NPRA) gene (Npr1) expression in vivo. We used all-trans retinoic acid (ATRA) and histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) to examine the expression and function of Npr1 using gene-disrupted heterozygous (1-copy; 1/2), wild-type (2-copy; 1/1), and gene-duplicated heterozygous (3-copy; 11/1) mice. Npr1 1/2 mice exhibited increased renal HDAC and reduced histone acetyltransferase (HAT) activity; on the contrary, Npr111/1 mice showed decreased HDAC and enhanced HAT activity compared with Npr1 1/1 mice. ATRA and NaBu promoted global acetylation of histones H3-K9/14 and H4-K12, reduced methylation of H3-K9 and H3-K27, and enriched accumulation of active chromatin marks at the Npr1 promoter. A combination of ATRA-NaBu promoted recruitment of activator-complex containing E26 transformation-specific 1, retinoic acid receptor a, and HATs (p300 and p300/cAMP response element-binding protein-binding protein-associated factor) at the Npr1 promoter, and significantly increased renal NPRA expression, GC activity, and cGMP levels. Untreated 1-copy mice showed significantly increased systolic blood pressure and renal expression of a-smooth muscle actin (a-SMA) and proliferating cell nuclear antigen (PCNA) compared with 2-and 3-copy mice. Treatment with ATRA and NaBu synergistically attenuated the expression of a-SMA and PCNA and reduced systolic blood pressure in Npr1 1/2 mice. Our findings demonstrate that epigenetic upregulation of Npr1 gene transcription by ATRA and NaBu leads to attenuation of renal fibrotic markers and systolic blood pressure in mice with reduced Npr1 gene copy number, which will have important implications in prevention and treatment of hypertension-related renal pathophysiological conditions.
Purpose: To assess patient satisfaction among current and former users of the antiinflammatory topical medications, cyclosporine A 0.05% (CYC) and lifitegrast 5.0% (LIF), for the management of dry eye disease (DED). Patients and Methods: Patients with DED were recruited via physician referral to participate in a survey. Current users of CYC or LIF were asked to rate their experience in terms of satisfaction, side effects, and limitation of activities. Switchers of CYC to LIF or LIF to CYC were asked to rate the importance of potential reasons for switching. Results: Surveys were completed by 207 patients currently treated with CYC (n=98), LIF (n=96), or other DED medications (n=13). Although overall satisfaction with current treatment was high, current users of CYC and LIF reported ineffective relief of DED symptoms (31% and 22%, respectively) and dissatisfaction with the time to onset of effect (29% and 11%). Substantial proportions of patients reported 'sometimes', "usually", or 'always' experiencing the following side effects: burning sensation (72% CYC, 64% LIF), itching (43% CYC, 44% LIF), altered sensation of taste (21% CYC, 56% LIF), blurred vision (37% CYC, 50% LIF), and discharge (28% CYC, 30% LIF). Of the 30 switchers of CYC to LIF and 31 switchers of LIF to CYC, the majority reported inability to relieve DED symptoms as a very or extremely important switching reason. Despite switching, one in four patients were somewhat dissatisfied or dissatisfied with their current medication, with 37% of patients reporting ineffective symptom relief. Conclusion: Although the rate of overall satisfaction was generally high with both LIF and CYC, many patients were unable to achieve effective symptom relief and commonly experienced side effects. The proportion of patients who were dissatisfied and/or unable to achieve effective symptom relief even after switching suggests the need for additional treatment options for managing DED.
Cell‐cycle regulatory proteins (p21Cip1/p27Kip1) inhibit cyclin and cyclin‐dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1/p27Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor‐A, GC‐A/NPRA) gene‐knockout (0‐copy; Npr1−/−), 2‐copy (Npr1+/+), and 4‐copy (Npr1++/++) mice treated with GC inhibitor, A71915 and cGMP‐dependent protein kinase (cGK) inhibitor, (Rp‐8‐Br‐cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0‐copy mice and A71915‐ and Rp‐treated 2‐copy and 4‐copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21Cip1, and p27Kip1 occurred in 0‐copy and A71915‐treated 2‐copy and 4‐copy mice, while Rp treatment caused minimal changes than controls. Pro‐inflammatory (TNF‐α, IL‐6) and pro‐fibrotic (TGF‐β1) cytokines were significantly increased in plasma and kidneys of 0‐copy and A71915‐treated 2‐copy mice, but to lesser extent in 4‐copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0‐copy and A71915‐treated 2‐copy and 4‐copy mice, but minimally occurred in Rp‐treated mice compared with controls. These results indicate that Npr1 has pivotal roles in inhibiting renal fibrosis and hypertrophy and exerts protective effects involving cGMP/cGK axis by repressing CDK blockers p21Cip1 and p27Kip1.
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