Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients

Abstract

Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes cytochrome-c oxidase-3 and NADH dehydrogenase subunit-1 by quantitative polymerase chain reaction in essential (n=25) and renovascular (RVH, n=34) hypertensive patients and compared them with healthy volunteers (n=22). Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin served as indices of renal injury. Renal blood flow and oxygenation were assessed by multidetector computed tomography and blood oxygen level-dependent magnetic resonance imaging. Blood pressure, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were similarly elevated in essential hypertension and RVH, and estimated glomerular filtration rate was lower in RVH versus healthy volunteers and essential hypertension. Renal blood flow was lower in RVH compared with essential hypertension. Urinary mtDNA copy number was higher in hypertension compared with healthy volunteers, directly correlated with urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 and inversely with estimated glomerular filtration rate. In RVH, urinary mtDNA copy number correlated directly with intrarenal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared with healthy volunteers (n=10 each). The change in serum creatinine levels and estimated glomerular filtration rate 3 months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.