Mitochondrial Dysfunction in Congenital Nephrotic Syndrome

Solin, Marja-Liisa; Pitkänen, Sari; Taanman, Jan‐Willem; Holthöfer, Harry

doi:10.1038/labinvest.3780130

Cited by 23 publications

(18 citation statements)

References 33 publications

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“…This finding is of clinical relevance to human glomerular disease. For example, Solin et al 43 reported that a reduction in mtDNA copy number in the kidney cortex accounts for MtD in Finnish type congenital nephrotic syndrome. Holthofer et al 44 also reported down-regulation of the mitochondrially encoded respiratory chain complex in glomeruli isolated from the same patients.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Zhu

Huang

Yuan

et al. 2011

The American Journal of Pathology

108

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Aldosterone (Aldo) causes podocyte damage by an unknown mechanism. We examined the role of mitochondrial dysfunction (MtD) in Aldo-treated podocytes in vitro and in vivo. Exposure of podocytes to Aldo reduced nephrin expression dose dependently, accompanied by increased production of reactive oxygen species (ROS). The ROS generation and podocyte damage were abolished by the mitochondrial (mt) respiratory chain complex I inhibitor rotenone. Pronounced MtD, including reduced mt membrane potential, ATP levels, and mtDNA copy number were seen in Aldo-treated podocytes and in the glomeruli of Aldo-infused mice. The mineralocorticoid receptor antagonist eplerenone significantly inhibited Aldo-induced MtD. The MtD was associated with higher levels of ROS, reduction in the activity of complexes I, III, and IV, and expression of the peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator-1␣ and mt transcription factor A. Both the PPAR␥ agonist rosiglitazone and PPAR␥ overexpression protected against podocyte injury by preventing MtD and oxidative stress, as evidenced by reduced ROS production, by maintenance of mt morphology, by restoration of mtDNA copy number, by decrease in mt membrane potential loss, and by recovery of mt electron transport function. The protective effect of rosiglitazone was abrogated by the specific PPAR␥ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPAR␥ agonist rosiglitazone may protect podocytes from this injury by The mineralocorticoid aldosterone (Aldo) is a key component of the renin-angiotensin-aldosterone system and is increasingly recognized as an important player in the development and progression of kidney disease. Patients with chronic kidney disease have markedly elevated plasma Aldo concentrations. Animal studies suggest that Aldo is a pathogenic factor in renal injury in the remnant kidney of hypertensive rats, 1 and in renal fibrosis. Moreover, exogenous infusion of Aldo reverses the renoprotective effects of angiotensin-converting enzyme inhibitors in hypertensive remnant kidney rats, and in stroke-prone, spontaneously hypertensive rats. 2 In vitro studies show that Aldo exerts a direct deleterious influence on kidney cells, including podocytes, 3-5 mesangial cells, proximal tubular epithelial cells, 6 and fibroblasts. In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury. 5,[7][8][9] However, the underlying mechanism for Aldoinduced injury in the kidney (in general) and in the podocytes (in particular) is not well understood.Podocytes are terminally differentiated, high-energy required cells that have lost mitotic activity, and typically do not proliferate after injury. 10 Mitochondria (mt) dysfunction (MtD) is involved in several diseases and progressive disease processes, including glomerulosclerosis, in which podocyte injury is a crucial event in sclerosis formation. 11,12 We hypothesized that preserving mt func...

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Zhu

Huang

Yuan

et al. 2011

The American Journal of Pathology

108

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“…Mitochondrial dysfunction and altered mitochondrial gene expression have also been documented in patients with NS secondary to nephrin mutations, 33,34 suggesting that, regardless of the initial insult, mitochondria play an important role in podocyte metabolism and may be actively involved in the pathophysiology of various forms of NS.…”

Section: Discussionmentioning

confidence: 99%

COQ2 Nephropathy

Diomedi-Camassei

Giandomenico

Santorelli

et al. 2007

Journal of the American Society of Nephrology

307

260

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Primary coenzyme Q 10 (CoQ 10 ) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ 10 synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [IIϩIII] and decreased CoQ 10 concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.

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“…Initial studies revealed altered expression of mitochondrial genes and mitochondrial dysfunction in acquired and congenital human nephrotic syndrome (3,4). Furthermore, collapsing FSGS has been associated with mitochondrial injury with inherited mutations in genes encoding for mitochondrial function (5).…”

Section: Introductionmentioning

confidence: 99%