Genetic and molecular mechanisms of arterial hypertension in relation to chronic inflammation, oxidative stress, and chronic kidney disease

• Název práce v češtině: Genetické a molekulární mechanizmy hypertenze ve vztahu k zánětu oxidačnímu stresu a chronickému renálnímu onemocnění
• Název v anglickém jazyce: Genetic and molecular mechanisms of arterial hypertension in relation to chronic inflammation, oxidative stress, and chronic kidney disease
• Klíčová slova: renální patofyziologie; metabolický syndrom; poměr albumin/kreatinin v moči; frakční exkrece kyseliny močové; uromodulin
• Klíčová slova anglicky: renal pathophysiology; metabolic syndrome; albumin/creatinine ratio; fractional excretion of uric acid; uromodulin
• Akademický rok vypsání: 2013/2014
• Typ práce: disertační práce
• Jazyk práce: angličtina
• Ústav: Institut klinické a experimentální medicíny (11-00020)
• Vedoucí / školitel: prof. MUDr. Renata Cífková, CSc.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 12.08.2014
• Datum zadání: 12.08.2014
• Datum potvrzení stud. oddělením: 12.08.2014
• Datum a čas obhajoby: 21.09.2017 10:00
• Místo konání obhajoby: Fyziologický ústav 1. LF UK, Albertov 5, 128 00 Praha 2
• Datum odevzdání elektronické podoby: 20.06.2017
• Datum proběhlé obhajoby: 21.09.2017
• Předmět: Obhajoba dizertační práce (B90002)
• Oponenti: prof. MUDr. Jiří Widimský, CSc.

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Předběžná náplň práce

Tato dizertační práce se zabývá metabolickým syndromem a patofyziologickými mechanizmy, které vysvětlují vztah mezi poklesem vylučování kyseliny močové ledvinami a albuminurií. Zpracovali jsme data z celkem dvou populačních studií. V první části jsme použili data z průřezového šetření reprezentativního vzorku české populace (studie Czech post-MONICA). Ukázali jsme, že u osob bez manifestního metabolického syndromu (MetS), ale s 1−2 kritérii MetS, je poměr albumin/kreatinin v moči (uACR) spojen se zvýšenou hladinou kyseliny močové v séru. Zároveň se hladina kyseliny močové v séru zvýšila synergickou interakcí mezi uACR s indexem viscerální adiposity a krevním tlakem. Ve druhé části jsme analyzovali data z reprezentativního vzorku populace Kanaďanů francouzského původu (studie CARTaGENE) s dostupnou detailnější analýzou moče. Tato studie přinesla dvě nová zjištění. Za prvé, ukázali jsme, že T alela rs13129697 polymorfizmu, která byla v dosud publikovaných pracích spojena se zvýšenou hladinou kyseliny močové v séru, je spojena s paradoxním poklesem uACR. Příčinou této diskrepance je interakce mezi rs13129697 genotypem a aktuální hodnotou FEUA, což podporuje hypotézu o tubulární výměně kyseliny močové za albumin. Za druhé, použitím mediační analýzy jsme prokázali, že pokles močové exkrece uromodulinu a sodíku vysvětluje až 70 % vztahu mezi poklesem FEUA a albuminurií, což dále zdůrazňuje roli porušené regulace krevního tlaku v tomto vztahu. Konečně, přidáním uACR společně s hladinou kyseliny močové v séru anebo FEUA k zavedeným složkám MetS jsme v obou populacích identifikovali dvě vzájemně související, ale jedinečné hlavní komponenty syndromu. S nepatrnými rozdíly vykazovaly první a druhá hlavní komponenta MetS srovnatelnou strukturu v obou studiích. Ve studii CARTaGENE vysvětlila močová exkrece uromodulinu 9 % korelace mezi hlavními komponentami MetS.
Lze tedy uzavřít, že pokles močové exkrece uromodulinu může být jedním z patofyziologických mechanizmů, který vysvětluje nejen pokles FEUA v přítomnosti albuminurie, ale i vztah mezi hlavními komponentami MetS.

Předběžná náplň práce v anglickém jazyce

This thesis provides an appraisal of the structure of clustering of metabolic phenotypes and evaluates the pathophysiological mechanisms underlying the relationship between urinary uric acid and albumin excretion. Two population-based studies were involved. In the first part, we used data obtained in a large representative cross-sectional survey in the Czech Republic (Czech post-MONICA study). We showed that the urinary albumin/creatinine ratio (uACR) was an independent factor for an increase in serum uric acid (SUA) levels in adults without manifest metabolic syndrome (MetS), but with 1–2 MetS component(s). Furthermore, SUA levels increased by the synergistic interaction of uACR with visceral adiposity and blood pressure, which may suggest obesity-related hypertension with altered renal hemodynamics as the primary mechanism. In the second part, we analyzed data captured in a representative population sample of French Canadians (CARTaGENE study) with more detailed urine biochemical analyses available. This study yielded two novel observations. First, we showed that the rs13129697 major T allele, which has been associated with increased SUA levels in our analysis as well as in prior publications, was associated with a paradoxical decrease in uACR. The reason for this discrepant finding is the interaction between rs13129697 genotype and the current rate of FEUA, suggesting tubular uric acid/albumin exchange. Second, using the mediation analysis approach, we propose that decreased urinary uromodulin and sodium excretion explain 70% of the relationship between decreased FEUA and increased uACR, which further supports the role of altered blood pressure regulation in this relationship. Finally, we identified two correlated but still unique principal components of the MetS and derived the principal component scores. With slight disparities, the first and second principal component scores exhibited comparable loading patterns between the studies. In the CARTaGENE study, urinary uromodulin explained 9% of the correlation between the principal component scores.
In conclusion, urinary uromodulin may not only be in a causal pathway between uric acid and albumin excretion but, also, to a much lesser extent, between the principal components of the MetS.