Renal pathology in children with mitochondrial diseases

Martín‐Hernández, Elena; García‐Silva, María Teresa; Vara, Julia; Campos, Yolanda; Cabello, Ana; Muley, Rafael; Hoyo, Pilar del; Martín, Miguel; Arenas, Joaquı́n

doi:10.1007/s00467-005-1948-z

Cited by 99 publications

(81 citation statements)

References 35 publications

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“…Indeed, in addition to the well-characterized cardiac dysfunction seen in this disorder, some individuals with Friedreich's ataxia develop renal disease. A role for mitochondria in the development of diabetic kidney disease is further strengthened by the recent observation that up to 50% of children with mitochondrial diseases have renal impairment (16). Furthermore, some of these subjects with mitochondrial respiratory chain defects have demonstrated renal disease as their primary pathology, including a newly described mitochondriopathy involving a deficiency in coenzyme Q10, which also has primary renal involvement (17).…”

Section: Mitochondrial Sources Of Rosmentioning

confidence: 99%

Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

2008

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It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.

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Section: Mitochondrial Sources Of Rosmentioning

confidence: 99%

Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

2008

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“…Renal manifestations of mitochondrial disease may be subclinical or overshadowed by other systemic symptoms, and therefore requires routine monitoring in patients with mitochondrial disease. In a review of 42 children with primary mitochondrial disease in 1 series, only 8 of them had overt symptoms of renal dysfunction, although a mild tubular disorder was present in 50 % of this population [141]. At the same time, patients with unexplained renal manifestations should have a mitochondrial evaluation, especially if there is other organ involvement.…”

Section: Kidneymentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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“…The proximal tubule (PT) is especially vulnerable to mitochondrial dysfunction from insults such as genetic mitochondrial cytopathy 4,6 or toxic xenobiotics (e.g., antiretroviral drugs 7,8 ). The reasons for this are not properly understood; in vivo, the PT is thought to depend mainly on aerobic metabolism for its energy supply, with very little anaerobic capacity compared with distal tubule (DT) segments.…”

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confidence: 99%

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Hall

Unwin

Parker

et al. 2009

Journal of the American Society of Nephrology

138

115

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Mitochondrial dysfunction may play a role in the pathogenesis of several renal diseases. Although functional roles and metabolic demands differ among tubule segments, relatively little is known about the properties of mitochondria in different parts of the nephron. Clinically, the proximal tubule seems particularly vulnerable to mitochondrial toxicity. In this study, we used multiphoton imaging of live rat kidney slices to investigate differences in mitochondrial function along the nephron. The mitochondrial membrane potential was markedly higher in distal than proximal tubules. Inhibition of respiration rapidly collapsed the membrane potential in proximal tubules, but potential was better maintained in distal tubules. Inhibition of the F 1 F o -ATPase abolished this difference, suggesting that maintenance of potential via ATPase activity is more effective in distal than proximal tubules. Immunostaining revealed that the ratio of the expression of ATPase to IF1, an endogenous inhibitor of the mitochondrial ATPase, was lower in proximal tubules than in distal tubules. Production of reactive oxygen species was higher in proximal than distal cells, but inhibition of NADPH oxidase eliminated this difference. Glutathione levels were higher in proximal tubules. Overall, mitochondria in the proximal tubules were in a more oxidized state than those in the distal tubules. In summary, there are axial differences in mitochondrial function along the nephron, which may contribute to the pattern and pathophysiology of some forms of renal injury.

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Renal pathology in children with mitochondrial diseases

Cited by 99 publications

References 35 publications

Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

Mitochondrial Disease in Childhood: Nuclear Encoded

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

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