Research Article: Dysregulation of microRNAs and renin-angiotensin system in high salt diet-induced cardiac dysfunction in uninephrectomized rats

Date Published: July 20, 2017

Publisher: Public Library of Science

Author(s): Venkateswara Rao Amara, Sunil Kumar Surapaneni, Kulbhushan Tikoo, Michael Bader.

http://doi.org/10.1371/journal.pone.0180490

Abstract

Uninephrectomy is not associated with major adverse events in cardiovascular and renal functions of live kidney donors. The effect of high salt diet on the quality of life of live kidney donors is largely unknown. Hence in this study, we aimed to determine the effect of high salt diet on the alterations of renin-angiotensin system and microRNAs leading to CV and renal dysfunction in uninephrectomized rats. In order to mimic clinical scenario, uninephrectomized male Sprague Dawley rats were fed initially with normal pellet diet for 12 weeks and then for 20 weeks with high salt (10% w/w NaCl) diet. At the end of the study, biochemical, functional, histological and molecular parameters were measured. High salt diet feeding resulted in renal dysfunction & fibrosis, decreased baroreflex sensitivity, increased in vivo cardiovascular reactivity to angiotensin II owing to upregulation of angiotensin II type 1 receptors and L-type calcium channels leading to cardiovascular dysfunction in uninephrectomized rats (UNX+HSD) worse than that of normal (binephric) rats fed with high salt diet (HSD). Protein expression of functional and hypertrophic protein markers revealed decreased SERCA, p-AMPK and increased p-AKT. Interestingly, levels of miR-25, miR-451 and miR-155 increased and miR-99 decreased in heart of uninephrectomized rats fed with high salt. However, circulating miR-25 and miR-451 levels decreased and miR-99b increased in these animals. Our study points out that since tissue and circulating levels of miRNAs are not similar, caution must be exercised during the usage of miRs as diagnostic or prognostic biomarkers. To our knowledge, we are the first to show that epigenetic alterations result in cardiac dysfunction in uninephrectomized rats fed with high salt diet.

Partial Text

Globally, cardiovascular diseases (CVDs)—ischemic heart disease and cerebrovascular disease are the number-one and two death-causing diseases for the past decade [1, 2]. With the exception of very insignificant genetic predisposition, the risk factors of CVDs are lifestyle-acquired including increased intake of salt, fructose, fat-rich foods, alcohol, smoking, physical inactivity, stress, etc. [3, 4].

Consumption of high sodium in the form of high dietary intake of salt (sodium chloride) has increased enormously across the globe posing the people at risk for both pressure-dependent and independent deleterious effects on various systems. With the increasing demand of renal transplants for patients suffering from ESRD, renal carcinoma etc, the numbers of live kidney donors are also rising alarmingly. To get an insight into the CV and renal functions of such live kidney donors consuming high salt diet, the present study was carried out to investigate the effect of high salt diet on the cardiac, vascular and renal functions in uninephrectomized rats with emphasis on renin angiotensin system (RAS) and epigenetic alterations. High salt elicited cardiovascular and renal-dysfunction and fibrosis, independent of hypertension, in binephric and uninephrectomized rats. To the best of our knowledge, we are the first to investigate the effect of high salt feeding on epigenetic alterations, the levels of tissue and circulating miRNAs and changes in local & systemic RAS in uninephrectomized rats. Our work is different from previous work [32, 33] as we initiated high salt diet feeding after a certain period of normal diet feeding post uninephrectomy, and hence mimics the clinical setting of live kidney donors in a better way.

Effect of high salt diet on the quality of life of kidney donors is largely unknown. In the present study, we show that high salt diet feeding led to cardiovascular and renal dysfunction in uninephrectomized rats implicating epigenetic alterations (microRNAs (miRs)) and renin angiotensin system (RAS). In a nutshell, our study demonstrated that uninephrectomy per se caused no adverse effects, but sensitized the animals to dietary manipulation (high salt diet feeding) culminating in exacerbated cardiac, vascular and renal dysfunction manifested by decreased baroreflex sensitivity, increased in vivo cardiovascular reactivity to Ang II and fibrosis in cardiac, vascular and renal tissue. This cardiac dysfunction is attributed to the activation of local RAS, altered cardiac miRNA-25, -99b, -155, -451 and their corresponding targeted proteins—SERCA2, p-AKT, and p-AMPK (Fig 6). Since the pattern of circulating miRs showed a pattern exactly opposite to that of the heart, caution must be exercised in utilizing them as clinical biomarkers.

 

Source:

http://doi.org/10.1371/journal.pone.0180490

 

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