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

Venkateswara Rao Amara,Sunil Kumar Surapaneni,Michael Bader,Kulbhushan Tikoo

doi:10.1371/journal.pone.0180490

Venkateswara Rao Amara, Sunil Kumar Surapaneni + Show 2 more

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

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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.

Highlights

Cardiovascular diseases (CVDs)—ischemic heart disease and cerebrovascular disease are the number-one and two death-causing diseases for the past decade [1, 2]
High salt diet deranges kidney function and instigates renal and cardiac hypertrophy There was no significant difference between normal control (Ctrl) and uninephrectomized (UNX) rats in terms of % BW change, plasma albumin, creatinine as long as the animals were on normal diet (Table 1)
After 20 weeks of high salt diet feeding, polyphagia, polydipsia, polyuria, wasting, lipolysis, increased systemic angiotensin II, renal dysfunction & cardiac hypertrophy were observed in rats fed with high salt diet (HSD) and uninephrectomized rats fed with high salt diet (UNX+HSD) compared to Ctrl and UNX groups (Table 2)

Summary

Introduction

Cardiovascular diseases (CVDs)—ischemic heart disease and cerebrovascular disease are the number-one and two death-causing diseases for the past decade [1, 2]. High salt evokes cardiovascular and renal dysfunction in uninephrectomy. Exception of very insignificant genetic predisposition, the risk factors of CVDs are lifestyleacquired including increased intake of salt, fructose, fat-rich foods, alcohol, smoking, physical inactivity, stress, etc. Majority of the reports did not find any major renal or cardiovascular complications in donor nephrectomized people even after many years of surgery [7, 8]. There are no reports showing the effect of diet-induced renal or cardiovascular complications in these donor nephrectomized patients

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