Rosiglitazone attenuates hypoxia-induced renal cell apoptosis by inhibiting NF-κB signaling pathway in a PPARγ-dependent manner.

BACKGROUND: In recent years, peroxisome proliferator-activated receptor γ (PPARγ) has been found to be closely associated with hypoxia renal disease. The aim of this study was to investigate the relationship between rosiglitazone and mitochondrial apoptosis in renal tissue and its associated mechanisms. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into three groups (n = 8 in each): normal control group, hypoxia injury group (equal volume of 0.9% saline), and PPARγ agonist group (Rosiglitazone, 10 mg/kg · d, intraperitoneally). The hypoxia injury group and PPARγ agonist group were placed in a hypoxia chamber and the simulated altitude was set at 7,000 m for 7 days. Blood and kidney samples were collected after 7 days. The quantitative real-time polymerase chain reaction and Western blot methods were used to determine the expression of PPARγ, nuclear factor kappa-B (NF-κB), B-cell lymphoma-2 (Bcl-2), and Bax. RESULTS: The results showed that compared with the normal control group, the renal tissue of rats after hypoxia was severely damaged, as shown by massive renal tubular epithelial cell degeneration and detachment, and renal tubular dilation. The NF-κB protein expression significantly increased, the Bcl-2 protein and mRNA expression significantly decreased, and Bax protein and mRNA expression significantly increased (p < .05 for all). Renal injury was much less severe in the PPARγ agonist group compared to the hypoxia injury group. CONCLUSIONS: Rosiglitazone can alleviate hypoxia renal injury, with the possible mechanism involving attenuation of apoptosis by inhibiting the activation of the NF-κB signaling pathway in a PPARγ-dependent manner and increasing Bcl-2 and decreasing Bax expression.

ATRA attenuate proteinuria via downregulation of TRPC6 in glomerulosclerosis rats induced by adriamycin.

OBJECTIVE: In this research, we explored the molecular mechanism of proteinuria in glomerulosclerosis rats and the protective effects of ATRA. METHODS: This research set up three groups: SHO group, GS group, and ATRA group (15 mg/(kg d), Sigma, St. Louis, MO). The serum creatinine (Scr), urea nitrogen (BUN), and 24-h proteinuria were detected 12 weeks after administration of ATRA. The pathological and ultrastructure changes were observed under light microscope and transmission electron microscope. The protein expression of TGF-ß1 and Col-IV in glomerulus was detected by immunohitochemistry method. The mRNA and the protein expression of glomerular TRPC6 were detected by RT-PCR and Western blot. RESULTS: In the rat model of GS, the expressions of TRPC6 were significantly elevated compared with the normal rat group; however, the use of ATRA down-regulated the expression of TRPC6 in the glomeruli and attenuated glomerulosclerosis and proteinuria. Scr and BUN were also improved by the treatment of ATRA. CONCLUSIONS: Our results demonstrated that ATRA could ameliorate glomerulosclerosis and proteinuria in GS, which may be related to suppressed expression of TRPC6.

Neutral endopeptidase and natriuretic peptide receptors participate in the regulation of C-type natriuretic peptide expression in renal interstitial fibrosis.

The initiation and progression of renal interstitial fibrosis (RIF) is a complicated process in which many factors may play an activate role. Among these factors, C-type natriuretic peptide (CNP) is an endothelium-derived hormone and acts in a local, paracrine fashion to regulate vascular smooth muscle tone and proliferation. In this study, we established a rat model of unilateral ureteral obstruction (UUO). CNP expression tends to be higher immediately after ligation and declined at later time points, occurring predominantly in tubular epithelial cells. A high-level CNP may contribute to the elevated expression of natriuretic peptide receptor (NPR)-B in the early phase of UUO. However, the sustained expression of NPR-C and neutral endopeptidase (NEP) observed throughout the study period (that is up to 3 months) helps to, at least partly, explain the subsequent decline of CNP. Thus, NEP and NPRs participate in the regulation of CNP expression in RIF.

[Research advances in the protective effect of all-trans retinoic acid against podocyte injury].

All-trans retinoic acid (ATRA) is a vitamin A derivative and plays an important role in the regulation of cell aggregation, differentiation, apoptosis, proliferation, and inflammatory response. In recent years, some progress has been made in the role of ATRA in renal diseases, especially its protective effect on podocytes. This article reviews the research advances in podocyte injury, characteristics of ATRA, podocyte differentiation and regeneration induced by ATRA, and the protective effect of ATRA against proliferation, deposition of fibers, and apoptosis.

Therapeutic effect of CNP on renal osteodystrophy by antagonizing the FGF-23/MAPK pathway.

Renal osteodystrophy (ROD) is highly prevalent in chronic kidney disease (CKD). Because most patients with ROD are asymptomatic in the early stage and bone biopsy remains not a routine procedure in many clinical settings; therefore, several biochemical parameters may help to identify the existence of ROD. C-type natriuretic peptide (CNP) is considered as a positive regulator of bone formation. Both urinary excretion and renal expression of CNP are markedly up-regulated in the early stages of CKD, whereas they are still progressively declined accompanied by CKD progression, which invites speculation that the progressive decline of CNP may contribute, in part, to the pathogenesis of ROD. In addition, fibroblast growth factor (FGF)-23 is a bone-derived endocrine regulator of phosphate homeostasis. The elevation of serum FGF-23 has been recognized as a common feature in CKD to maintain normophosphatemia at the expense of declining 1,25-dihydroxyvitamin D values. Since the effects of CNP and FGF-23 on bone formation appear to oppose each other, it is reasonable to propose a direct interaction of their signaling pathways during the progression of ROD. CNP and FGF-23 act through a close or reciprocal pathway and are in agreement with recent studies demonstrating a down-regulatory role of the mitogen-activated protein kinase activity by CNP. The specific node may act at the level of RAF-1 through the activation of cyclic guanosine monophosphate-dependent protein kinases II.

Exogenous C-type natriuretic peptide infusion ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis in rats.

Although many experimental therapeutic roles for C-type natriuretic peptide (CNP) have been documented in the field of cardiovascular and pulmonary-vascular disease, the therapeutic uses of CNP to nephropathies are not as well documented. In this study, we established a rat model of unilateral ureteral obstruction (UUO) to observe the beneficial effects of CNP on tubulointerstitial fibrosis (TIF). In UUO rats, CNP administration induced a significant increase in plasma CNP levels, and caused a significant decrease in blood urea nitrogen and creatinine levels. In addition, CNP infusion also alleviated the pathological lesions and collagen IV accumulation in the obstructed kidneys through downregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression. In conclusion, exogenous CNP infusion can ameliorate UUO-induced TIF in rats. However, the use of CNP as a therapeutic agent requires further evaluation before being considered for human TIF.

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.

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).

GSTT1 polymorphism and the risk of developing prostate cancer.

A possible association between glutathione S-transferase theta 1 gene (GSTT1) polymorphism and the risk of developing prostate cancer is currently hotly debated, but evidence from various epidemiologic studies remains unclear. This investigation was performed to assess whether an association between GSTT1 polymorphism and prostate cancer risk exists by using meta-analysis to combine comparable studies, thereby increasing sample size and statistical significance, as well as to identify patterns in various studies. The association reports were identified from the PubMed database and the Cochrane Library on March 1, 2013, and data from eligible studies (from 1999-2012) were synthesized. Thirty-eight reports were included in this meta-analysis on the association of the null genotype of GSTT1 with prostate cancer risk. No solid association between the GSTT1 null genotype and prostate cancer risk could be established for the overall population (odds ratio = 1.11, 95% confidence interval: 0.97, 1.27; P = 0.13). However, the GSTT1 null genotype was distinctly associated with prostate cancer risk in Caucasians (odds ratio = 1.24, 95% confidence interval: 1.03, 1.48, P = 0.02). In conclusion, the GSTT1 null genotype is associated with prostate cancer risk in Caucasians, but not in the overall population.

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.

Potential signal pathway of all-trans retinoic acid for MMP-2 and MMP-9 expression in injury podocyte induced by adriamycin.

All-trans-retinoic acid (ATRA) can regulate some specific genes expression in various tissue and cells via nuclear retinoic acid receptors (RARs), including three subtypes: retinoic acid receptor-alpha (RAR-α), retinoic acid receptor-beta (RAR-ß) and retinoic acid receptor-gamma (RAR-γ). Podocyte injury plays a pivotal role in the progression of glomerulosclerosis (GS). This study was performed to study the potential signal pathway of ATRA in the expression of matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases-9 (MMP-9) in injury podocyte. Cells were divided into three groups: group of negative control (NC), group of injury podocyte induced by adriamycin (ADR) (AI) and group of ADR inducing podocyte injury model treated with ATRA (AA). The cells morphology changes were detected using microscope and scanning electron microscopy. MMP-2 and MMP-9 enzymic activity was detected using the gelatin zymography method. Protein and mRNA expressions of MMP-2, MMP-9, RAR-α, RAR-ß and RAR-γ were measured by western-blot and real-time RT-PCR. Enzymatic activity of MMP-2 and MMP-9 in group AA was significantly enhanced compared to AI group after ATRA-treated 24 h (p < 0.05). The protein and mRNA expressions of MMP-2/MMP-9 in group AA were significantly increased than those in group AI at both 12 and 24 h time points (p < 0.05). Compared to group AI, RAR-α and RAR-γ protein/mRNA expressions of group AA were significantly increased at both 12 and 24 h time points (p < 0.05). There was no difference for the expression of RAR-ß between group AI and group AA (p > 0.05). RAR-α protein level was positively correlated with MMP-2 or MMP-9 protein expression (p < 0.05), and RAR-γ protein level was also positively correlated with MMP-2 or MMP-9 protein expression (p < 0.05). In conclusion, ATRA may increase expression of MMP-2 and MMP-9 by the potential signal pathway of RAR-α and RAR-γ in injury podocyte induced by adriamycin, but not RAR-ß.

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.

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.

Retracted Association of STAT4 gene polymorphism with systemic lupus erythematosus / lupus nephritis risk.

OBJECTIVE: The association of STAT4 gene polymorphism with systemic lupus erythematosus (SLE) / lupus nephritis (LN) results from the published studies is still conflicting. This meta-analysis was performed to evaluate the relationship between STAT4 rs7574865, rs16833431, rs11889341, rs8179673, rs10168266, rs7582694, rs3821236, rs7601754 gene polymorphism and SLE / LN, and to explore whether STAT4 gene polymorphism could become a predictive marker for SLE / LN risk. METHODS: Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of September 1, 2013, and eligible investigations were synthesized using meta-analysis method. RESULTS: 24 investigations were identified for the analysis of association between STAT4 gene polymorphism and SLE, consisting of 31190 patients with SLE and 43940 controls. In STAT4 rs7574865, there was a marked association between T allele or TT genotype and SLE susceptibility (T: OR=1.53, 95% CI: 1.30-1.79, P<0.00001; TT: OR=1.60, 95% CI: 1.34-1.92, P<0.00001), and GG homozygous was associated with SLE risk (OR=0.62, 95% CI: 0.51-0.75, P<0.00001). Furthermore, rs8179673, rs7582694, or rs3821236 minor allele frequency was associated with the risk of SLE, but this association was not found in rs16833431, rs11889341, rs10168266, rs7601754, however, the number of included studies was small and the results were less robust. In addition, STAT4 rs7574865 gene polymorphism was not associated with the LN risk. CONCLUSIONS: Our results indicate that T allele or TT homozygous is a significant risk genetic molecular marker to predict the SLE susceptibility and GG genotype is a valuable marker to against the SLE risk, but the association was not found for LN. However, more investigations are required to further clarify the association of the T allele or TT homozygous with SLE / LN susceptibility.

Association of transforming growth factor-ß1 T869C gene polymorphism with diabetic nephropathy risk.

AIM: A possible association between the transforming growth factor-ß1 (TGF-ß1) T869C gene polymorphism and the risk of developing diabetic nephropathy (DN) remains unclear. This investigation was performed to assess if an association between the TGF-ß1 T869C gene polymorphism and DN risk exists by using meta-analysis to combine comparable studies, thereby increasing sample size and statistical significance, and to identify patterns in various studies. METHODS: The association reports were identified from PubMed, Cochrane Library, and CBM-disc (China Biological Medicine Database) on 1 May 2013, and eligible studies were recruited and synthesized. RESULTS: Fifty reports were recruited into this meta-analysis for the association of the TGF-ß1 T869C gene polymorphism with DN risk. The TT genotype in the overall population was shown to be associated with DN risk (odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.56-0.98, P = 0.04). In the sub-group analysis, CC genotype was associated with DN risk in Asians, Caucasians, and Africans. However, the sample size for Caucasians and Africans was relatively small. Furthermore, T allele was distinctly associated with the risk of developing DN in the Asian population (OR = 0.76, 95% CI: 0.62-0.92, P = 0.005). CONCLUSIONS: The TT genotype of TGF-ß1 T869C in the overall population was associated with DN risk, whereas the CC genotype and T allele were distinctly associated with DN risk in the Asian population. Nonetheless, additional studies are required to firmly establish a correlation between the aforementioned polymorphism and DN risk.

Signaling pathways of prohibitin and its role in diseases.

Prohibitin (PHB), appearing to be a negative regulator of cell proliferation and to be a tumor suppressor, has been connected to diverse cellular functions including cell cycle control, senescence, apoptosis and the regulation of mitochondrial activities. It is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria and cytoplasmic compartments. However, in different tissues/cells, the expression of PHB was different, such as that it was increased in most of the cancers, but its expression was reduced in kidney diseases. Signaling pathways might be very important in the pathogenesis of diseases. This review was performed to provide a relatively complete signaling pathways flowchart for PHB to the investigators who were interested in the roles of PHB in the pathogenesis of diseases. Here, we review the signal transduction pathways of PHB and its role in the pathogenesis of diseases.

Association of peroxisome proliferator-activated receptors/retinoic acid receptors with renal diseases.

Peroxisome proliferator-activated receptor-γ (PPARγ), belongs to the nuclear receptor superfamily, and is a nuclear transcription receptor involving in the regulation of several biochemical pathways, such as cell growth, differentiation, and apoptosis. The nuclear retinoic acid receptors (RARs) are transcriptional transregulators that control the expression of specific subsets of genes in a ligand-dependent manner, and include three subtypes (RARα, RARß, and RARγ). These control the expression of specific gene subsets subsequent to ligand binding and to strictly control phosphorylation processes. The current status of knowledge indicates that there might be inter- or overlapping actions between PPARγ and RARs, and there might be an association of PPARγ/RARs with renal diseases. Various agonists of both receptor families seem to prevent or retard the progression of renal disease. Herein, we review if causal relationships can be established between PPARγ/RARs and renal diseases and its manifestations.

Association of angiotensinogen M235T gene polymorphism with end-stage renal disease risk: a meta-analysis.

Association between angiotensinogen (AGT) M235T gene polymorphism and end-stage renal disease (ESRD) risk is still controversial. This meta-analysis was performed to evaluate the association of AGT M235T gene polymorphism with ESRD susceptibility. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases of PubMed, Embase and Cochrane Library. Sixteen literatures were identified for the analysis of association of AGT M235T gene polymorphism with ESRD risk. T allele and TT genotype were associated with ESRD susceptibility in Caucasians (T: OR = 1.13, 95 % CI: 1.02-1.25, P = 0.02; TT: OR = 1.22, 95 % CI: 1.03-1.45, P = 0.02). However, MM genotype might not play a protective role against ESRD risk in Caucasians. Furthermore, there was no a markedly positive association between AGT M235T gene polymorphism and ESRD susceptibility in overall populations, Asians and Africans. In conclusion, T allele or TT homozygote is associated with the onset of ESRD in Caucasians. However, more studies should be performed in the future.

Anti-neutral endopeptidase, natriuretic peptides disarrangement, and proteinuria onset in membranous nephropathy.

Neutral endopeptidase (NEP) is the first podocytic antigen responsible for human membranous nephropathy (MN). Besides the prevailing pathogenetic mechanism of immune complex, NEP is also involved in the metabolism of natriuretic peptides (NP). The identification of anti-NEP antibodies in human MN suggests that the decreased circulating NEP may down-regulate the NP catabolism. In this context, we hypothesize that NP disarrangement secondary to anti-NEP antibodies may account, in part, for the onset of proteinuria in MN. Whereas the pathways for the onset of proteinuria caused by elevated NP level are still obscure. The data presented in this review focus on those which support this hypothesis with regards to evidence from the glomerular haemodynamic changes, endothelial permeability, glomerular basement membrane disruption, and podocyte detachment.

Overexpressed C-type natriuretic peptide serves as an early compensatory response to counteract extracellular matrix remodeling in unilateral ureteral obstruction rats.

Although the mechanism underlying C-type natriuretic peptide (CNP) beneficial effects is not entirely understood, modulating the expression of matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) may play an important role. The study presented herein was designed as a first demonstration of the regulative effects of CNP on MMPs/TIMPs expression in unilateral ureteral obstruction (UUO) rats. The continuous changes of CNP, MMP-2, MMP-9, TIMP-1, TIMP-2 and type IV collagen (Col-IV) expression were determined in the obstructed rat kidneys at 3 days, 1, 2, and 3 months post-UUO respectively. According to the real-time PCR analysis, CNP, MMP-2 and MMP-9 mRNA expression in the obstructed kidneys were significantly higher compared to every time corresponding SOR, and progressively decreased over time. In contrast, in the obstructed kidneys collected 2 and 3 months post-UUO, the higher TIMP-1 and TIMP-2 mRNA expression were observed in comparison to the corresponding SOR group. The above trends of CNP, MMP-2, MMP-9, TIMP-1, and TIMP-2 transcripts were confirmed by their protein expression based on immunohistochemistry and western blot, and finally contributed to the progressive elevated Col-IV expression in the obstructed kidneys throughout the entire study period. Overexpressed CNP may be an early compensatory response to counteract extracellular matrix remodeling in UUO rats.