Lysosome restoration to activate podocyte autophagy: a new therapeutic strategy for diabetic kidney disease.

Autophagy, the intracellular lysosomal degradation process plays a pivotal role in podocyte homeostasis in diabetic kidney disease (DKD). Lysosomal function, autophagic activity, and their actions were investigated in vitro and in vivo. We found that LC3-II- and p62-positive vacuoles accumulated in podocytes of patients with DKD. Moreover, we found that advanced glycation end products (AGEs) could increase the protein expression of LC3-II and p62 in a dose- and time-dependent manner in cultured podocytes. However, the mRNA expression of LC3B, Beclin-1 or ATG7, as well as the protein level of Beclin-1 or ATG7 did not change significantly in the AGE-treated cells compared with that in control groups, suggesting that AGEs did not induce autophagy. In addition, AGEs led to an increase in the number of autophagosomes but not autolysosomes, accompanied with a failure in lysosomal turnover of LC3-II or p62, indicating that the degradation of autophagic vacuoles was blocked. Furthermore, we observed a dramatic decrease in the enzymatic activities, and the degradation of DQ-ovalbumin was significantly suppressed after podocytes were treated with AGEs. Plasma-irregular lysosomal-associated membrane protein 1 granules accompanied with the diffusion of cathepsin D expression and acridine orange redistribution were observed in AGE-treated podocytes, indicating that the lysosomal membrane permeability was triggered. Interestingly, we also found that AGEs-induced autophagic inhibition and podocyte injury were mimicked by the specific lysosomotropic agent, L-leucyl-L-leucine methyl ester. The exacerbated apoptosis and Rac-1-dependent actin-cytoskeletal disorganization were alleviated by an improvement in the lysosomal-dependent autophagic pathway by resveratrol plus vitamin E treatment in AGE-treated podocytes. However, the rescued effects were reversed by the addition of leupeptin, a lysosomal inhibitor. It suggests that restoring lysosomal function to activate autophagy may contribute to the development of new therapeutic strategies for DKD.

p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation.

The ubiquitin-proteasome system (UPS) and autophagy are two distinct and interacting proteolytic systems. They play critical roles in cell survival under normal conditions and during stress. An increasing body of evidence indicates that ubiquitinated cargoes are important markers of degradation. p62, a classical receptor of autophagy, is a multifunctional protein located throughout the cell and involved in many signal transduction pathways, including the Keap1-Nrf2 pathway. It is involved in the proteasomal degradation of ubiquitinated proteins. When the cellular p62 level is manipulated, the quantity and location pattern of ubiquitinated proteins change with a considerable impact on cell survival. Altered p62 levels can even lead to some diseases. The proteotoxic stress imposed by proteasome inhibition can activate autophagy through p62 phosphorylation. A deficiency in autophagy may compromise the ubiquitin-proteasome system, since overabundant p62 delays delivery of the proteasomal substrate to the proteasome despite proteasomal catalytic activity being unchanged. In addition, p62 and the proteasome can modulate the activity of HDAC6 deacetylase, thus influencing the autophagic degradation.

The potential signaling pathway between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha in renal interstitial fibrosis disease.

Peroxisome proliferator-activated receptorγ (PPARγ) can regulate the process of cell apoptosis and is related to the progression of renal disorders. Retinoic acid receptor alpha (RARα) is one of the nuclear receptors involved in a variety of kidney diseases. Renal interstitial fibrosis (RIF) is a common denominator of chronic kidney disease (CKD). This study investigated whether a potential signaling pathway existed between PPARγ and RARα in RIF rats with unilateral ureteral obstruction (UUO). The rats were randomly divided into four groups: a model group subjected to UUO (GU), and three other groups treated with rosiglitazone sodium (GRS), GW9662 and dimethyl sulfoxide (DMSO), n = 40, respectively. Renal tissues were collected two and four weeks after post-surgery. The relevant indicators were detected. In comparison with the GU group, the expressions of PPARγ and RARα (protein and mRNA) were increased in the GRS group, and decreased in the GW9662 group (all p < 0.01). The RIF index, mRNA and protein expression of transforming growth factor-ß1 (TGF-ß1), and the protein expressions of collagen-IV (Col-IV) and fibronectin (FN) in the GRS group were more markedly reduced than those in the GU group; their levels in the GW9662 group were elevated (all p < 0.01). PPARγ or RARα was negatively correlated to the RIF index, TGF-ß1, Col-IV and FN. PPARγ was positively correlated with RARα (all p < 0.01). In conclusion, PPARγ agonist can elevate the expression of PPARγ or RARα in RIF rats. There might be a potential signaling pathway between PPARγ and RARα in RIF disease.

The role of retinoic acid receptors in the signal pathway of all-trans retinoic acid-induced differentiation in adriamycin-induced podocyte injury.

All-trans retinoic acid (ATRA) plays an essential role in cell survival and differentiation by binding to retinoic acid receptors (RARs), including RAR-α, RAR-ß, and RAR-γ. Injury to podocytes is the most frequent cause of glomerulosclerosis (GS). This study was performed to investigate which of the RAR subtypes is involved in the signal pathway of ATRA-induced differentiation of injured podocytes. ATRA (0.1 µM) was administered to Adriamycin (ADR)-induced, injured podocytes, in vitro. Morphological changes were observed. The protein/mRNA expression of podocin, nephrin, transforming growth factor ß1(TGF-ß1), and the RARs (RAR-α,ß,γ) was measured by RT-PCR and Western blotting. ATRA treatment ameliorated cell hypertrophy and reduced the shedding of the cytoplasm which was observed under light microscope and the extension of the foot processes was observed under scan electron microscope. Compared with the injured podocytes, ATRA exposure significantly increased the protein/mRNA expression of nephrin and podocin and it markedly reduced TGF-ß1 (all p < 0.05). Compared with the injured podocytes, the protein/mRNA expression of RAR-α and RAR-γ was significantly increased after ATRA exposure; however, the expression level of RAR-ß was not significantly different. The RAR-α/γ protein expression level was positively correlated with nephrin and podocin (-α, r = 0.637, 0.663; -γ, r = 0.882, 0.878; all p < 0.05), and negatively correlated with TGF-ß1 (-α, r = -0.650; -γ, r = -0.739; all p < 0.05). The RAR-ß protein expression level was not correlated with nephrin, podocin and TGF-ß1 (r = -0.312, 0.079, -0.279; all p > 0.05). In conclusion, RAR-α/γ (and RAR-ß to a lesser degree) may be involved in the signal pathway of ATRA-induced differentiation in injured podocytes.

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats.

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM homeodomain type and has been implicated in the development of diverse structures such as limbs, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30% of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and renal interstitial fibrosis, we explored if LMX1B affects typical markers of fibrosis, e.g., extracellular matrix components, profibrotic factors, and apoptosis as the final detrimental consequence. We recently showed that LMX1B acts as a negative regulator of transforming growth factor-ßl, collagen type III, fibronectin, cleaved caspase-3, and the cell apoptosis rate in a renal tubular epithelial cell system under hypoxic conditions. Here, we confirmed these results in unilateral ureteral obstructed rats. Furthermore, LMX1B was distinctly expressed throughout the glomerulus and tubule lining, including epithelial cells. Knockdown of LMX1B aggravated the expression of fibrosis markers, oxidative stress, and apoptosis compared with the already increased levels due to unilateral ureteral obstruction, whereas overexpression attenuated these effects. In conclusion, reduced LMX1B levels clearly represent a risk factor for renal fibrosis, whereas overexpression affords some level of protection. In general, LMX1B may be considered to be a negative regulator of the fibrosis index, transforming growth factor-ßl, collagen type III, fibronectin, cleaved caspase-3, cell apoptosis, ROS, and malondialdehyde (r = -0.756, -0.698, -0.921, -0.923, -0.843, -0.794, -0.883, and -0.825, all P < 0.01).

Association of prohibitin-1 and 2 with oxidative stress in rats with renal interstitial fibrosis.

Prohibitins PHB1 and PHB2 are evolutionary conserved and pleiotropic proteins, which have been shown to be important factors in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Recently, we demonstrated that down-regulation promoted renal interstitial fibrosis (RIF) in ureteral obstructed rats. Furthermore, the hypoxic conditions and oxidative stress have been implicated in obstruction-mediated renal disease. This study was performed to explore the association of PHBs with oxidative stress in a rat model of RIF. PHBs, the pro-fibrotic transforming growth factor-ß1 (TGF-ß1), and the extracellular matrix proteins collagen-IV (Col-IV) and fibronectin (FN) were evaluated, as were markers of oxidative stress [total reactive oxygen species (ROS), malondialdehyde (MDA)] and antioxidative capacity (superoxide dismutase, glutathione), and apoptosis. Our results showed a progressive increase in oxidative stress and concomitant decrease in antioxidants over a period of 4 weeks ureteral obstruction. Concomitantly, profibrotic components increased and PHB expression decreased. Overall, both PHBs were negatively correlated with the extent of observed fibrosis, TGF-ß1, Col-IV, FN, ROS, MDA, and apoptosis.

LIM homeobox transcription factor 1B is associated with pro-fibrotic components and apoptosis in hypoxia/reoxygenation renal tubular epithelial cells.

LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM-homeodomain type, which plays an important role in foetal development during formation of the extremities, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30 % of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and pro-fibrotic components and apoptosis in hypoxic renal tubular epithelial cells (RTEC), we explored if LMX1B was associated with extracellular matrix components, profibrotic factors, and apoptosis induced by hypoxia/reoxygenation (H-R). In this cell system under hypoxic conditions, when the expression of LMX1B was inhibited in H-R RTEC, the expression of transforming growth factor-ßl, collagen-III, fibronectin, cleaved caspase-3, and cell apoptosis rate was increased. Consequently, overexpression of LMX1B was associated with reduced cell apoptosis, whilst downregulation of LMX1B was associated with increased cell apoptosis in H-R RTEC.

Prohibitin is associated with antioxidative protection in hypoxia/reoxygenation-induced renal tubular epithelial cell injury.

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. We recently demonstrated that prohibitin downregulation results in increased renal interstitial fibrosis. Here we investigated the role of oxidative stress and prohibitin expression in a hypoxia/reoxygenation injury system in renal tubular epithelial cells with lentivirus-based delivery vectors to knockdown or overexpress prohibitin. Our results show that increased prohibitin expression was negatively correlated with reactive oxygen species, malon dialdehyde, transforming-growth-factor-ß1, collagen-IV, fibronectin, and apoptosis (r = -0.895, -0.764, -0.798, -0.826, -0.817, -0.735; each P < 0.01), but positively correlated with superoxide dismutase, glutathione and mitochondrial membrane potential (r = 0.807, 0.815, 0.739; each P < 0.01). We postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Prohibitin attenuates oxidative stress and extracellular matrix accumulation in renal interstitial fibrosis disease.

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Both prohibitin over- and under-expression have been implicated in various diseases and cell types. We recently demonstrated that prohibitin down-regulation results in increased renal interstitial fibrosis (RIF). Here we investigated the role of oxidative stress and prohibitin expression in RIF in unilateral ureteral obstructed rats. Lentivirus-based delivery vectors were used to knockdown or over-express prohibitin. Our results show that increased prohibitin expression was negatively correlated with the RIF index, reactive oxygen species, malon dialdehyde, transforming growth factor ß1, collagen IV, fibronectin, and cell apoptosis index. In conclusion, we postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Association of PAX2 with cell apoptosis in unilateral ureteral obstruction rats.

Renal interstitial fibrosis (RIF) is the final common pathway for chronic kidney disease. Cell apoptosis is a critical detrimental event that leads to renal fibrosis. Paired box 2 (PAX2) plays a major role in the development of the kidney. This study was performed to investigate whether PAX2 was associated with cell apoptosis in the progression of RIF in unilateral ureteral obstruction (UUO) rats. Eighty Wistar male rats were divided into two groups randomly: sham operation group (SHO) and model group subjected to UUO (GU), n = 40, respectively. The model was established by left ureteral ligation. Renal tissues were collected 14 and 28 days after surgery. Protein expressions of PAX2, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), collagen-IV (Col-IV), fibronectin (FN), and caspase-3 were detected using immunohistochemical analysis; mRNA expression of PAX2 in renal tissue was detected by real-time reverse transcription polymerase chain reaction; and RIF index and cell apoptosis index in renal interstitium were also calculated. When compared with those in the SHO group, expressions of PAX2 (protein and mRNA) were markedly increased in the GU group (each p < 0.01). Protein expressions of TGF-ß1, α-SMA, Col-IV, FN, and caspase-3 and RIF index and cell apoptosis index in the GU group were remarkably increased when compared with those in the SHO group (each p < 0.01). The protein expression of PAX2 was positively correlated with the protein expressions of TGF-ß1, α-SMA, Col-IV, FN, and caspase-3 and with RIF index and cell apoptosis index (all p < 0.01). The apoptotic cell in our observation was mainly derived from renal tubular epithelial cells. In conclusion, the increased expression of PAX2 is associated with cell apoptosis in the progression of RIF in UUO rats, suggesting that PAX2 is a potentially therapeutic target for prevention of RIF. Tian-Biao Zhou and Yuan-Han Qin wish it to be known that, in their opinion, they should be regarded as joint first authors.

A meta-analysis of the association between angiotensin-converting enzyme insertion/deletion gene polymorphism and steroid-sensitive nephrotic syndrome in children.

BACKGROUND AND OBJECTIVE: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism correlates with circulating and cellular ACE concentration. Association between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) risk in children is still controversial. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and SSNS susceptibility in children. METHODS: The relevant investigations were screened from the search engines of PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) as of 1 March 2011, and eligible studies were synthesized using meta-analysis methods. RESULTS: Ten studies were identified for the analysis of association between ACE I/D gene polymorphism and SSNS risk in children, including seven in Asians, one for Caucasians and two in Africans. There was no markedly positive association between D allele or DD genotype and SSNS susceptibility in Asians, Caucasians and Africans (D: Asians OR = 1.24, p = 0.28; Caucasians OR = 1.61, p = 0.15; Africans OR = 1.61, p = 0.53; DD: Asians OR = 1.72, p = 0.15; Caucasians OR = 1.39, p = 0.48; Africans OR = 1.80, p = 0.56). Furthermore, II homozygous seemed not to play a protective role against SSNS onset for Asians, Caucasians and Africans (Asians OR = 0.95, p = 0.85; Caucasians OR = 0.30, p = 0.11; Africans OR = 0.60, p = 0.65). CONCLUSIONS: There was no association between ACE I/D gene polymorphism and SSNS susceptibility in Asians, Caucasians and Africans. However, the conclusions for Caucasians and Africans were less powerful.

Less expression of prohibitin is associated with increased caspase-3 expression and cell apoptosis in renal interstitial fibrosis rats.

AIMS: Prohibitin (PHB), a ubiquitous protein, is involved in a variety of molecular functions. Renal interstitial fibrosis (RIF) is a hallmark of common progressive chronic diseases that lead to renal failure. This study was performed to investigate whether PHB was associated with caspase-3 expression/cell apoptosis in RIF rats. METHODS: Twenty-four male Wistar rats were randomly divided into two groups: sham operation group (SHO) and model group subjected to unilateral ureteral obstruction (GU), n = 12, respectively. The model was established by left ureteral ligation. Renal tissues were collected at 14 days and 28 days after surgery. RIF index, cell apoptosis index, protein expression of PHB, transforming growth factor-ßl (TGF-ß1), collagen-IV (Col-IV), fibronectin (FN) or caspase-3 in renal interstitium, and mRNA expression of PHB in renal tissue were detected. RESULTS: Compared with that in the SHO group, the PHB expression (mRNA and protein) was significantly reduced (P < 0.01). Protein expressions of TGF-ß1, Col-IV, FN and caspase-3, and RIF index or cell apoptosis index in GU group were markedly elevated compared with those in SHO group (all P < 0.01). The protein expression of PHB had a negative correlation with the protein expression of TGF-ß1, Col-IV, FN or caspase-3, and RIF index or cell apoptosis index (each P < 0.01). CONCLUSIONS: Less expression of PHB is associated with increased caspase-3 expression/cell apoptosis in RIF rats. However, further research is needed to determine the effect of PHB on caspase-3 expression/cell apoptosis and to determine the potential of PHB as a therapeutic target.

Less gelatinases is associated with apolipoprotein E accumulation in glomerulosclerosis rats.

BACKGROUND: Gelatinases include matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The abnormal expressions of gelatinases are implicated in the pathogenesis of extracellular matrix (ECM) accumulation. Apolipo-protein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the progression of glomerulosclerosis (GS). We conducted this investigation to explore whether gelatinases were associated with the apoE accumulation in the pathological process of GS. METHODS: 40 Wistar rats were divided into two groups at random: sham operation group (SHO) and glomerulosclerosis model group (GS); n=20, respectively. The disease of GS was established by uninephrectomy and adriamycin (5 mg/kg) injection. At the end of 13 weeks, the 20 rats in each group were killed and the relevant samples were collected and measured. RESULTS: Serum total protein (TP) and serum albumin (Alb) in GS group were reduced compared to those of the SHO group (P<0.01). Compared with the SHO group, values of 24-hour urine total protein (24UTP), 24-hour urine excretion for albumin (24Ualb), blood urea nitrogen (BUN), serum creatinine (Scr) and glomerulosclerosis index (GSI) in GS group were significantly increased (P<0.01). The protein of MMP-2 or MMP-9 in the glomerulus, and mRNA expression of MMP-2 or MMP-9 in renal tissue were reduced when compared with those in SHO (P<0.01). Protein expressions of apoE, collagen IV (Col-IV), fibronectin (FN), α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1) in the glomerulus and expression of apoE mRNA in renal tissue were significantly up-regulated in GS group when compared with those in the SHO group (P<0.01). CONCLUSIONS: Lower expression of gelatinases is associated with the increased expression of apoE in the glomerulus, and increases the accumulation of ECM and takes part in the pathological change of GS.

All-trans retinoic acid can regulate the expressions of gelatinases and apolipoprotein E in glomerulosclerosis rats.

Apolipoprotein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the pathogenesis of glomerulosclerosis (GS). Gelatinases include matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The abnormal expressions of gelatinases are implicated in the pathogenesis of extracellular matrix accumulation. All-trans retinoic acid (ATRA) is an import biological agent which can play a protective role against GS. We performed this investigation to explore whether ATRA could regulate the expressions of gelatinases and apoE in the glomerulus of GS rats. 120 Wistar rats were randomly divided into three groups: sham operation group (SHO), glomerulosclerosis model group without treatment (GS) and GS model group treated with ATRA (GA). The GS disease was established by uninephrectomy and adriamycin injection. At the end of 9 and 13 weeks, the relevant samples were collected and determined. Compared with GS group at 9/13 weeks, values of 24-hour urine total protein, 24-hour urine excretion for albumin, blood urea nitrogen, serum creatinine and glomerulosclerosis index, and protein expressions of apoE, transforming growth factor-ßl (TGF-ß1), α-smooth muscle actin, collagen-IV and fibronectin in glomerulus and mRNA expressions of apoE and TGF-ß1 in renal tissue were significantly down-regulated by ATRA (each P<0.01). However, the expressions of MMP-2 and MMP-9 (mRNA, protein and activity) were enhanced in GA group than those in GS group. In conclusion, gelatinases are associated with apoE expression, and ATRA can increase the gelatinases expressions and reduce the accumulation of apoE in glomerulus of GS rats, but the detailed mechanism needs to be elucidated in the future.

Association of angiotensin converting enzyme insertion/deletion gene polymorphism with idiopathic nephrotic syndrome susceptibility in children: a meta-analysis.

BACKGROUND AND OBJECTIVE: Angiotensin converting enzyme (ACE) gene contains either an insertion (I) allele or a deletion (D) allele forming three potential genotypes: II, ID and DD. The D allele or DD genotype has been reported to be associated with higher plasma ACE level. An assessment of the association between ACE I/D gene polymorphism and idiopathic nephrotic syndrome (INS) susceptibility in children is still controversial. This meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and the onset of INS. METHOD: A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases, and eligible investigations were synthesized using the meta-analysis method. RESULTS: Nine investigations were identified for the analysis of association between ACE I/D gene polymorphism and INS risk in children, including six in Asians, one study for Caucasians and two for Africans. There was positive association between D allele or DD genotype and INS susceptibility in Asians (OR = 1.75, p = 0.01; OR = 2.01, p = 0.02), but not for Caucasian children and Africans (for Caucasians, D: OR=1.35, p = 0.27, DD: OR = 0.95, p = 0.91; for Africans, D: OR = 1.70, p = 0.56, DD: OR = 1.60, p = 0.73). Furthermore, II homozygous seemed to play a positive role against INS onset for Asians (OR = 0.59, p = 0.02), but the link between II genotype and INS risk was not observed in Caucasian children and Africans (Caucasians: OR = 0.31, p = 0.06; Africans: OR = 0.50, p = 0.59). CONCLUSIONS: D allele and DD homozygous might become significant genetic molecular markers for INS susceptibility in Asian children, but the association was not observed in Caucasians or Africans. However, the conclusion from our study cannot be sustained and more investigations on larger sample in different populations are required to further clarify the role of D allele or DD homozygous in the onset of INS in difference races.

Insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme gene in steroid-resistant nephrotic syndrome for children: a genetic association study and meta-analysis.

An assessment of the association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with steroid-resistant nephrotic syndrome (SRNS) risk in children is still controversial. A meta-analysis was performed to evaluate the relation between ACE gene polymorphisms and SRNS susceptibility. The relevant studies were screened from electronic database and eligible investigations were synthesized using meta-analysis methods. Seven investigations were identified for the analysis of association between ACE I/D gene polymorphism and SRNS risk in children, including five in Asians, one in Caucasians, and one in Africans. There was not a markedly positive association between D allele or DD genotype and SRNS susceptibility in Asians (OR = 1.60, p = 0.26; OR = 1.90, p = 0.38) and for Caucasian population (OR = 0.92, p = 0.86; OR = 0.27, p = 0.22). However, an association of D allele with SRNS susceptibility was observed (OR = 4.67, p = 0.003) in Africans, but not for DD genotype (OR = 6.00, p = 0.05). Interestingly, II genotype seemed to play a positive role against SRNS onset for Asians and African children (OR = 0.51, p = 0.02; OR = 0.07, p = 0.02), but not for Caucasians (OR = 0.33, p = 0.30). In conclusion, our results indicate that D allele or DD homozygous might not be a significant genetic molecular marker for the development of SRNS in Asians and Caucasian children. However, D allele seemed be associated with SRNS risk for Africans but DD genotype did not.

The association between angiotensin-converting enzyme insertion/deletion gene variant and risk of focal segmental glomerulosclerosis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism with the risk of focal segmental glomerulosclerosis (FSGS) is still controversial. A meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and FSGS susceptibility. METHOD: We performed a predefined literature search and selection of eligible relevant studies to collect data from electronic databases. RESULTS: In total, 12 articles were identified for the analysis of the association between ACE I/D gene polymorphism and FSGS risk. One report included an investigation in Arab and Jewish populations separately. Thus, there were seven reports in Asians, two in Caucasians, one in Africans, two in Arabs and one in Jews. In Asians, there was a markedly positive association between the D allele or DD genotype and FSGS susceptibility (p = 0.008; p = 0.002), and the II genotype may play a protective role against FSGS onset (p = 0.002). However, a link between ACE I/D gene polymorphism and FSGS risk was not found in Caucasians, Africans, Arabs or Jews (Caucasians: D: p = 0.11, DD: p = 0.19, II: p = 0.70; Africans: D: p = 0.40, DD: p = 0.49, II: p = 0.61; Arabs: D: p = 0.34, DD: p = 0.10, II: p = 0.42; Jews: D: p = 0.90, DD: p = 0.97, II: p = 0.83). CONCLUSION: The D allele or DD homozygosity may become a significant genetic molecular marker for the onset of FSGS in Asians, but not for Caucasians, Africans, Arabs or Jews.

Relationship between Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism and Susceptibility of Minimal Change Nephrotic Syndrome: A Meta-Analysis.

Aim. This meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and MCNS susceptibility. Method. A predefined literature search and selection of eligible relevant studies were performed to collect the data from electronic databases. Results. Six articles were identified for the analysis of association between ACE I/D gene polymorphism and MCNS risk, including 4 for Asians, one in Caucasian population and one for Africans. There was a markedly positive association between D allele or DD genotype and MCNS susceptibility in Asians (D: P = .01, DD: P = .02), but not for Caucasians and Africans (Caucasians: D: P = .16, DD: P = .98; Africans: D: P = .81, DD: P = .49). Furthermore, the II genotype seemed not to play a protective role against MCNS risk for Asians, Caucasians and Africans (P = .12, P = .09, P = .76, resp.). Interestingly, there was also significant association between ACE I/D gene polymorphism and MCNS susceptibility in overall populations (D: P = .007, DD: P = .04, II: P = .03). Conclusion. D allele or DD genotype might be a significant genetic molecular marker for MCNS susceptibility in Asians and overall populations, but not for Caucasians and Africans. More larger and rigorous genetic epidemiological investigations are required to further explore this association.

ACE I/D gene polymorphism can't predict the steroid responsiveness in Asian children with idiopathic nephrotic syndrome: a meta-analysis.

BACKGROUND: The results from the published studies on the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the treatment response to steroid in Asian children with idiopathic nephrotic syndrome (INS) is still conflicting. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and treatment response to steroid in Asian children and to explore whether ACE D allele or DD genotype could become a predictive marker for steroid responsiveness. METHODOLOGY/PRINCIPAL FINDINGS: Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of September 1, 2010, and eligible investigations were synthesized using meta-analysis method. Five investigations were identified for the analysis of association between ACE I/D gene polymorphism and steroid-resistant nephrotic syndrome (SRNS) risk in Asian children and seven studies were included to explore the relationship between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) susceptibility. Five investigations were recruited to explore the difference of ACE I/D gene distribution between SRNS and SSNS. There was no a markedly association between D allele or DD genotype and SRNS susceptibility or SSNS risk, and the gene distribution differences of ACE between SRNS and SSNS were not statistically significant. II genotype might play a positive role against SRNS onset but not for SSNS (OR = 0.51, P = 0.02; OR = 0.95, P = 0.85; respectively), however, the result for the association of II genotype with SRNS risk was not stable. CONCLUSIONS/SIGNIFICANCE: Our results indicate that D allele or DD homozygous can't become a significant genetic molecular marker to predict the treatment response to steroid in Asian children with INS.

All-trans retinoic acid regulates the expression of apolipoprotein E in rats with glomerulosclerosis induced by Adriamycin.

Apolipoprotein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the progression of glomerulosclerosis (GS). We conducted this investigation to explore whether all-trans retinoic acid (ATRA) could regulate the apoE expression in the pathological process of GS. 120 Wistar rats were divided into three groups at random: sham operation group (SHO), glomerulosclerosis model group without treatment (GS), GS model group treated with ATRA (GA); n=40, respectively. The disease of GS in rat was established by uninephrectomy and adriamycin (5mg/kg) injection. At the end of 9 and 13 weeks, 20 rats in each group were killed and the relevant samples were collected. 24-hour urine total protein (24UTP), 24-hour urine excretion for albumin (24Ualb), serum total protein (TP) and serum albumin (Alb), blood urea nitrogen (BUN), serum creatinine (Scr), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), serum and urine apoE and glomerulosclerosis index (GSI) were measured. The protein expressions of collagen IV (Col-IV), fibronectin (FN) and apoE in glomeruli were determined by immunohistochemistry. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to detect the expression of apoE mRNA in kidney. TP and Alb in GA group in 9/13-week were increased than those of GS group, however, the differences were not statistically significant. Compared with group GS at 9/13 weeks, values of 24UTP, 24Ualb, BUN, Scr, TC, TG, HDL, LDL, serum and urine apoE, and GSI in GA group that were significantly reduced, and protein expressions of Col-IV, FN and apoE in glomeruli and expression of apoE mRNA in renal tissue were significantly down-regulated by ATRA (P<0.01). In conclusion, ATRA can regulate the expression of apoE, reduce the accumulation of extracellular matrix (ECM) and step down the progression of GS.