Role of mitochondria in paricalcitol-mediated cytoprotection during obstructive nephropathy

Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
AJP Renal Physiology (Impact Factor: 3.25). 04/2012; 302(12):F1595-605. DOI: 10.1152/ajprenal.00617.2011
Source: PubMed


Vitamin D slows the progression of chronic kidney disease. Furthermore, activators of vitamin D receptors (VDR) have suppressant effects on the renin-angiotensin system, as well as anti-inflammatory and antifibrotic actions. This study aimed to evaluate the cytoprotective effects of paricalcitol, a VDR activator, at the mitochondrial level using an obstructive nephropathy model [unilateral ureteral obstruction (UUO)]. Rats subjected to UUO and controls were treated daily with vehicle or paricalcitol. The control group underwent a sham surgery. The treatment was done for 15 days (30 ng/kg). The following were determined: biochemical parameters; fibrosis; apoptosis; mitochondrial morphology; VDR, AT(1) receptor, and NADPH oxidase 4 expression; and NADPH oxidase activity (in total and in mitochondrial fractions from the renal cortex). VDR activation prevented fibrosis (20 ± 5 vs. 60 ± 10%) and the number of TUNEL-positive apoptotic cells (10 ± 3 vs. 25 ± 4) in UUO. Biochemical, histological, and molecular studies suggest mitochondrial injury. Electron microscopy revealed in UUO electronically luminous material in the nucleus. Some mitochondria were increased in size and contained dilated crests and larger than normal spaces in their interiors. These changes were not present with paricalcitol treatment. Additionally, high AT(1)-receptor mRNA and NADPH activity was reverted in mitochondrial fractions from obstructed paricalcitol-treated animals (0.58 ± 0.06 vs. 0.95 ± 0.05 relative densitometry units and 9,000 ± 800 vs. 15,000 ± 1,000 relative fluorescence units·μg protein(-1)·min(-1), respectively). These changes were consistent with an improvement in VDR expression (0.75 ± 0.05 vs. 0.35 ± 0.04 relative densitometry units). These results suggest that paricalcitol confers a protective effect and reveal, as well, a possible AT(1) receptor-dependent protective effect that occurs at the mitochondrial level.


Available from: Walter Manucha
  • Source
    • "Results from animal model studies have suggested the potential renoprotective effects of active vitamin D and its analogues (Table 1) [33,34,35,36,37,38,39,40,41,42,43,44,45]. Beyond its role in calcium and phosphate homeostasis, vitamin D is an important modulator of cellular proliferation, inflammation, differentiation, and immunity [33,46,47]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic kidney disease (CKD) has been recognized as a significant global health problem because of the increased risk of total and cardiovascular morbidity and mortality. Vitamin D deficiency or insufficiency is common in patients with CKD, and serum levels of vitamin D appear to have an inverse correlation with kidney function. Growing evidence has indicated that vitamin D deficiency may contribute to deteriorating renal function, as well as increased morbidity and mortality in patients with CKD. Recent studies have suggested that treatment with active vitamin D or its analogues can ameliorate renal injury by reducing fibrosis, apoptosis, and inflammation in animal models; this treatment also decreases proteinuria and mortality in patients with CKD. These renoprotective effects of vitamin D treatment are far beyond its classical role in the maintenance of bone and mineral metabolism, in addition to its pleiotropic effects on extra-mineral metabolism. In this review, we discuss the altered metabolism of vitamin D in kidney disease, and the potential renoprotective mechanisms of vitamin D in experimental and clinical studies. In addition, issues regarding the effects of vitamin D treatment on clinical outcomes are discussed.
    The Korean Journal of Internal Medicine 07/2014; 29(4):416-427. DOI:10.3904/kjim.2014.29.4.416 · 1.43 Impact Factor
  • Source
    • "Consistently, MNADK expression levels are nutritionally regulated in liver and fat, and are altered in liver tumors. MNADK is also abundant in the heart, muscle, brown fat and kidney, all of which are known to be rich in mitochondria, because mitochondria are needed to produce large amount of energy for mechanical work in heart and muscle (Pagel-Langenickel et al., 2010), for heat production in brown fat (Jacobsson et al., 1985), and for waste excretion in the kidney (García et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: NADP(+) and its reducing equivalent NADPH are essential for counteracting oxidative damage. Mitochondria are the major source of oxidative stress, since the majority of superoxide is generated from the mitochondrial respiratory chain. Because NADP(+) cannot pass through the mitochondrial membrane, NADP(+) generation within mitochondria is critical. However, only a single human NAD kinase (NADK) has been identified, and it is localized to the cytosol. Therefore, sources of mitochondrial NADP(+) and mechanisms for maintaining its redox balance remain largely unknown. Here, we show that the uncharacterized human gene C5ORF33, named MNADK (mouse homologue 1110020G09Rik), encodes a novel mitochondrion-localized NAD kinase. In mice MNADK is mostly expressed in the liver, and also abundant in brown fat, heart, muscle and kidney, all being mitochondrion-rich. Indeed, MNADK is localized to mitochondria in Hep G2 cells, a human liver cell line, as demonstrated by fluorescence imaging. Having a conserved NAD kinase domain, a recombinant MNADK showed NAD kinase activity, confirmed by mass spectrometry analysis. Consistent with a role of NADP(+) as a coenzyme in anabolic reactions, such as lipid synthesis, MNADK is nutritionally regulated in mice. Fasting increased MNADK levels in liver and fat, and obesity dramatically reduced its level in fat. MNADK expression was suppressed in human liver tumors. Identification of MNADK immediately suggests a model in which NADK and MNADK are responsible for de novo synthesis of NADP(+) in cytosol and mitochondria, respectively, and therefore provides novel insights into understanding the sources and mechanisms of mitochondrial NADP(+) and NADH production in human cells.
    Biology Open 04/2013; 2(4):432-8. DOI:10.1242/bio.20134259 · 2.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kidney apoptosis and fibrosis are an inevitable outcome of progressive chronic kidney diseases where congenital obstructive nephropathy is the primary cause of the end-stage renal disease in children, and is also a major cause of renal failure in adults. The injured tubular cells linked to interstitial macrophages, and myofibroblasts produce cytokines and growth factors that promote an inflammatory state in the kidney, induce tubular cell apoptosis, and facilitate the accumulation of extracellular matrix. Angiotensin II plays a central role in the renal fibrogenesis at a very early stage leading to a rapid progression in chronic kidney disease. The increasing levels of angiotensin II induce pro-inflammatory cytokines, NF-κB activation, adhesion molecules, chemokines, growth factors, and oxidative stress. Furthermore, growing evidence reports that angiotensin II (a pro-inflammatory hormone) increases the mitochondrial oxidative stress regulating apoptosis induction. This review summarizes our understanding about possible mechanisms that contribute to apoptosis modulated by inflammation and/or oxidative stress during obstructive nephropathy. The new concept of antiinflammatory tools regulating mitochondrial oxidative stress will directly affect the inflammatory process and apoptosis. This idea could have attractive consequences in the treatment of renal and other inflammatory pathologies.
    04/2012; 11(4):303-12. DOI:10.2174/187152812800958997
Show more