Genetic associations between genes in the renin-angiotensin-aldosterone system and renal disease: a systematic review and meta-analysis

Abstract

BackgroundChronic kidney disease (CKD) is defined by abnormalities in kidney structure and/or function present for more than 3 months. Worldwide, both the incidence and prevalence rates of CKD are increasing. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance through the kidney. RAAS activation is associated with hypertension, which is directly implicated in causation and progression of CKD. RAAS blockade, using drugs targeting individual RAAS mediators and receptors, has proven to be renoprotective.ObjectivesTo assess genomic variants present within RAAS genes, ACE, ACE2, AGT, AGTR1, AGTR2 and REN, for association with CKD.Design and data sourcesA systematic review and meta-analysis of observational research was performed to evaluate the RAAS gene polymorphisms in CKD using both PubMed and Web of Science databases with publication date between the inception of each database and 31 December 2018. Eligible articles included case–control studies of a defined kidney disease and included genotype counts.Eligibility criteriaAny paper was removed from the analysis if it was not written in English or Spanish, was a non-human study, was a paediatric study, was not a case–control study, did not have a renal disease phenotype, did not include data for the genes, was a gene expression-based study or had a pharmaceutical drug focus.ResultsA total of 3531 studies were identified, 114 of which met the inclusion criteria. Genetic variants reported in at least three independent publications for populations with the same ethnicity were determined and quantitative analyses performed. Three variants returned significant results in populations with different ethnicities at p<0.05: ACE insertion, AGT rs699-T allele and AGTR1 rs5186-A allele; each variant was associated with a reduced risk of CKD development.ConclusionsFurther biological pathway and functional analyses of the RAAS gene polymorphisms will help define how variation in components of the RAAS pathway contributes to CKD.

Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel In Silico Method

“…It was proposed that ACE inhibitors could have both potentially harmful and beneficial effects on COVID-19. Membrane-bound angiotensin-converting enzyme 2 (ACE2) participates in the entry of SARS-CoV-2 into human cells, and animal studies show that ACE inhibitors could upregulate ACE2 expression; and on the other side, the beneficial effect can be expected with upregulated ACE2 converting angiotensin II to angiotensin-(1–7), with potentially advantageous vasodilatory and anti-inflammatory properties [ 29 , 30 ]. We can assume that ACE inhibitors through M pro inhibition, in addition to the already assumed theory of the advantageous effect of upregulated ACE2, could explain that treatment with ACE-inhibitors is associated with less severe disease in SARS-CoV-2 infection [ 31 ].…”

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

“…By contract, ACE2 inactivates angiotensin II while generating angiotensin 1-7, a heptapeptide having a potent vasodilator function via activation of its Mas receptor (Santos et al, 2003), and thus serving as a negative regulator of the renin-angiotensin system. These opposing actions of ACE and ACE2 were recently reviewed by Smyth, Cañadas-Garre, Cappa, Maxwell, & McKnight, 2019. The AT1R antagonists losartan and olmesartan, commonly applied for reducing blood pressure in hypertensive patients, were shown to increase cardiac ACE2 expression about three-fold following chronic treatment (28 days) after myocardial infarction induced by coronary artery ligation of rats (Ishiyama et al, 2004). Losartan was also shown to upregulate renal ACE2 expression in chronically treated rats (Klimas et al, 2015).…”

An Update on Current Therapeutic Drugs Treating COVID-19

“…It is speculated that SARS-CoVand SARS-CoV-2 bind to human cells via interaction with ACE2 receptors [118,119]. The opposing physiological actions of ACE and ACE2 in the renin-angiotensin system are reviewed to determine the therapeutic efficacy of ACE2 inhibitors or ARBs [120,121]. In hypertensive patients, chronic treatment with angiotensin II type 1 receptor (AT1R) antagonists like losartan, lisinopril, or olmesartan facilitates cardiac and renal ACE2 overexpression according to some in vivo studies [120,122].…”

“…The opposing physiological actions of ACE and ACE2 in the renin-angiotensin system are reviewed to determine the therapeutic efficacy of ACE2 inhibitors or ARBs [120,121]. In hypertensive patients, chronic treatment with angiotensin II type 1 receptor (AT1R) antagonists like losartan, lisinopril, or olmesartan facilitates cardiac and renal ACE2 overexpression according to some in vivo studies [120,122]. In contrast, SAR viral RNA following entry into respiratory epithelial cells downregulates the activity of ACE2, thereby increasing the levels of angiotensin 2.…”