TRPM2 Levels Research Articles

Liver Protection of Hydroxytyrosol Mediated by Spexin and TRPM2

Background/Aim: In the study, the role of Spexin (SPX) and TRPM2 in the protective effect of Hydroxytyrosol (HT) in rats given Corn Syrup was evaluated.
 Material and Method: The rats were divided into 4 groups (6 rats in each) (Control, HT, Corn Syrup, Corn Syrup +HT). Rats were given 30% Corn Syrup with drinking water for 6 weeks. 4 ml/kg/day liquid containing HT was applied by oral gavage alone and together with Corn Syrup for 6 weeks. Molecular parameters SPX and TRPM2 were examined histopathologically in liver tissue. 
 Results: The SPX levels decreased and the TRPM2 levels increased more in the Corn Syrup given Group than the Control Group. SPX levels increased and TRPM2 levels decreased after HT treatment. In the HT Group only, no differences were detected when compared to the control Group.
 Conclusion: SPX and TRPM2 may mediate the protective effect of HT on the liver in rats given corn syrup.

Examination of the effect of bupivacaine on brain tissue in rats with induced experimental renal failure

Background/Aim: Local anesthetics are frequently used and often considered harmless, but they can precipitate local anesthetic systemic toxicity (LAST) when accidentally administered intravascularly or when a toxic dose is rapidly absorbed, which can result in mortality. In cases of renal function impairment, the altered pharmacokinetics of local anesthetics lead to a lowered toxicity threshold. In this study, the aim was to histopathologically investigate the increase in neurotoxicity in the central nervous system due to bupivacaine in experimental renal failure. Methods: In the study, a total of 28 male Wistar albino rats, aged 8-10 weeks, were evenly divided into four groups: Group C (control group) received intraperitoneal 1 mL/kg saline; Group G (glycerol group) received intramuscular 10 mL/kg glycerol, Group GB (glycerol+bupivacaine group) received intramuscular 10 mL/kg glycerol followed by intraperitoneal 4 mg/kg bupivacaine; and Group B (bupivacaine group) received intraperitoneal 4 mg/kg bupivacaine. All rats were sacrificed after the experimental period. Tissue samples were preserved and stained with hematoxylin-eosin for histopathological analyses. TRPM2 and Reelin levels in brain tissue were measured using immunohistochemical methods. Results: In the histopathological examination, Group G exhibited higher Reelin and TRPM2 levels compared to all other groups (P<0.001). In Group GB, both Reelin and TRPM2 immunoreactivity were significantly higher compared to Group B (P<0.001). Conclusion: It can be concluded that renal dysfunction increases neurotoxicity in brain tissue associated with bupivacaine.

Resveratrol may reduce oxidative stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating meteorin-like and TRPM2 levels

Resveratrol may reduce oxidative stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating meteorin-like and TRPM2 levels

Interferon Gamma-Mediated Oxidative Stress Induces Apoptosis, Neuroinflammation, Zinc Ion Influx, and TRPM2 Channel Activation in Neuronal Cell Line: Modulator Role of Curcumin.

Host defenses in the brain are modulated by the activation of several factors such as oxygen free radical species (ROS), Ca2+ influx, and TRPM2 activation, and they are well-known adverse factors in neurotoxicity and neurodegenerative diseases. Importantly, recent data indicated a protective action of curcumin (CRC) via inhibition of TRPM2 on the inflammation factors, ROS, and apoptosis in hypoxia-induced SH-SY5Y neuronal cells. However, the relationship between interferon gamma (IFNg) exposure and TRPM2 activation in the SH-SY5Y cells are not fully identified. The SH-SY5Y cells as a neuronal cell line model were used in several neuroinflammation studies. Hence, we used the SH-SY5Y cells in the current study, and they were divided into four main groups as control, CRC, IFNg, and IFNg+CRC. The data presented here indicate that IFNg induced excessive Ca2+ influx via activation of TRPM2. The IFNg treatment further increased cell death, cell debris amount, apoptosis, and cytokine generations (IL-1β, IL-6, and TNF-α) which were due to increased cytosolic and mitochondrial ROS generations as well as increased activations of caspase-3 and caspase-9. The expression levels of TRPM2, PARP-1, Bax, caspase-3, and caspase-9 were increased in the cells by the IFNg treatment. However, CRC treatment reduced the increase of expression levels, cytokine generations, caspase activations, ROS release, Ca2+ influx, cell death, and apoptosis levels via inhibition of TRPM2 in the SH-SY5Y cells that were treated with IFNg. Moreover, the treatment of TRPM2 blockers (ACA and 2-APB) potentiated the modulator effects of CRC. In conclusion, these results suggest that neuroinflammation via IFNg lead to the TRPM2 activation in the SH-SY5Y cells, whereas CRC prevents IFNg-mediated TRPM2 activation, cell death, and cytokine generations.

MicroRNA-145-5p Protects Human Melanocytes Against Oxidative Damage by Targeting Transient Receptor Potential Melastatin 2 (TRPM2)

Background: Oxidative stress was reported to be involved in the progression of vitiligo. microRNAs (miRNAs) have been confirmed to display critical roles in vitiligo. In this study, we conjectured that miR-145-5p might be related to the development of vitiligo by regulating the key genes expression in melanocytes. Methods: H2O2 was used to induce the dysfunction of melanocytes. The levels of TRPM2 and miR-145-5p in H2O2-induced human primary melanocytes were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). TargetScan and Dual luciferase reporter gene assay were conducted to confirm the correlation between miR-145-5p and TRPM2. Cell viability and apoptosis were determined using MTT and Flow cytometry analysis. Reactive oxygen species (ROS), antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were determined using specific assay kits. The levels of cleaved caspase-3 and pro-Caspase3 were measure by western blotting. Results: TRPM2 was upregulated while miR-145-5p was downregulated in H2O2-induced human primary melanocytes. Dual luciferase reporter assay confirmed that TRPM2 was a target gene of miR-145-5p. miR-145-5p mimic transfection significantly increased cell viability and inhibited cell apoptosis in H2O2-treated melanocytes. In addition, overexpression of miR-145-5p enhanced the antioxidant activity of SOD and CAT, and decreased intracellular ROS accumulation. Notably, these findings were abolished by TRPM2-plasmid. Conclusions: Taken together, our study demonstrated that oxidative stress induced up-regulation of TRPM2 and down-regulation of miR-145-5p in melanocytes. In addition, overexpression of miR-145-5p alleviated melanocytes destruction via targeting TRPM2. These results indicated that miR-145-5p might serve as a potential target for anti-oxidative therapy in vitiligo.

Curcumin Attenuates Hypoxia-Induced Oxidative Neurotoxicity, Apoptosis, Calcium, and Zinc Ion Influxes in a Neuronal Cell Line: Involvement of TRPM2 Channel.

Apoptosis/cell death and reactive oxygen species (ROS) via overload free Ca2+ and Zn2+ uptake into mitochondria are emerging as crucial events in the etiology of hypoxia (HPX)-induced neurodegenerative diseases. The neuroprotective actions of curcumin (CURC) via modulation of oxidative stress and the PARP1-dependent activated TRPM2 cation channel on the ROS generation and cell death in several neurons have been recognized. However, the molecular mechanisms underlying CURC's neuroprotection remain elusive. We investigated the role of CURC via modulation of TRPM2 on cell death and oxidative cytotoxicity in SH-SY5Y neuronal cells. The SH-SY5Y cells were divided into five groups as follows: CURC (10µM for 24h), HPX (200µM CoCl2 for 24h), CURC+HPX, and HPX+TRPM2 blockers (2-APB-100µM or ACA-25µM for 30min). In some experiments, the cells in the HPX groups were additionally incubated with PARP1 (PJ34) and Zn2+ (TPEN) inhibitors. The exposure of CoCl2 induced increases of TRPM2 current density and Ca2+ fluorescence intensity with an increase of mitochondrial membrane depolarization and ROS generation. When HPX-induced TRPM2 activity was blocked by 2-APB and ACA, or the cells were treated with CURC, the increase of ROS generation, the expression levels of TRPM2 and PARP1 were restored. The levels of apoptosis and cell death in the cells were enriched with increases of caspase-3 and -9 activations, although they were decreased by CURC treatment. HPX-induced increase of cytosolic Zn2+ was attenuated by the TPEN and CURC treatments. In conclusion, CURC attenuates HPX-induced mitochondrial ROS generation, apoptosis, cell death, and TRPM2-mediated Ca2+ signaling and may provide an avenue for treating HPX-induced neurological diseases associated with the ROS, Ca2+, and Zn2+.

TRPM2-AS promotes cancer cell proliferation through control of TAF15.

Colorectal cancer (CRC) ranks the third among all common malignancy worldwide. Long noncoding RNAs (lncRNAs) have been demonstrated as implicated in CRC, but the roles of many lncRNAs in CRC remain unclear. Exploration of lncRNA TRMP2-AS and its nearby gene in CRC progress was the focus of current study. The expression of TRPM2-AS and its nearby mRNA TRPM2 was measured by using RT-qPCR. The protein levels of TRPM2 and TAF15 were determined using western blot. Cell proliferation was detected by using CCK-8, colony formation and EdU assays. The interaction between TAF15 and TRPM2-AS or TRPM2 was evaluated by RNA pull-down and RIP assays. The TRPM2 mRNA stability was probed using the transcriptional inhibitor Actinomycin D. TRPM2-AS was significantly upregulated in CRC cells. Knock-down of TRPM2-AS inhibited CRC cell proliferation. Mechanically, TRPM2-AS directly interacted with RNA-binding protein (RBP) TAF15 and thus maintained the mRNA stability of TRPM2. TRPM2 was a prerequisite for TRPM2-AS to exert its promoting function in CRC cell proliferation. This research demonstrated that TRPM2-AS facilitated proliferation of CRC cells by enhancing TAF15-mediated mRNA stability of TRPM2, unmasking the role of TRPM2-AS in CRC.

TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression.

In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H2O2 in a contact-dependent mechanism, thereby inducing a lethal Ca2+ influx via the activation of the H2O2-dependent TRPM2 Ca2+ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanisms-downregulation of neutrophil chemoattractants and blocking of the apoptotic Ca2+-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy.

Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity.

We have recently shown that neutrophil antitumor cytotoxicity is Ca2+ dependent and is mediated by TRPM2, an H2O2-dependent Ca2+ channel. However, neutrophil antitumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state. We found that TRPM2 expression was upregulated during epithelial-to-mesenchymal transition (EMT), and mesenchymal cells were more susceptible to neutrophil cytotoxicity. Conversely, cells undergoing mesenchymal-to-epithelial transition (MET) expressed reduced levels of TRPM2, rendering them resistant to neutrophil cytotoxicity. Cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These data identify TRPM2 as the link between environmental cues at the primary tumor site, tumor cell susceptibility to neutrophil cytotoxicity, and disease progression. Furthermore, these data identify EMT as a process enhancing tumor-cell immune susceptibility and, by contrast, MET as a novel mode of immune evasion.Significance: EMT is required for metastatic spread and concomitantly enhances tumor cell susceptibility to neutrophil cytotoxicity. Cancer Res; 78(17); 5050-9. ©2018 AACR.

TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells.

Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2 We report here that neutrophil cytotoxicity is Ca2+ dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ channel. Perturbing TRPM2 expression limited tumor cell proliferation, leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung.Significance: These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread. Cancer Res; 78(10); 2680-90. ©2018 AACR.

The effects of hydrated C(60) fullerene on gene expression profile of TRPM2 and TRPM7 in hyperhomocysteinemic mice

Background: Hyperhomocysteinemia (HHcy) is associated with neurodegenerative diseases. Transient receptor potential melastatin (TRPM2) and TRPM7 channels may be activated by oxidative stress. Hydrated C(60) fullerene (C(60)HyFn) have recently gained considerable attention as promising candidates for neurodegenerative states. We aimed to examine the effects on TRPM2 and TRPM7 gene expression of C(60)HyFn due to marked antioxidant activity in HHcy mice. Methods: C57BL/6 J. mice were divided into four groups: (1) Control group, (2) HHcy, (3) HHcy + C(60)HyFn-treated group and (4) C(60)HyFn-treated group. TRPM2 and TRPM7 gene expression in brains of mice were detected by real-time PCR, Western blotting and immunohistochemistry. Apoptosis in brain were assessed by TUNEL staining. Results: mRNA expression levels of TRPM2 were significantly increased in HHcy group compared to the control group. C(60)HyFn administration significantly decreased serum levels of homocysteine and TRPM2 mRNA levels in HHcy + C(60)HyFn group. Whereas, HHcy-treatment and C(60)HyFn administration did not change the expression of TRPM7. Conclusion: Administration of C(60)HyFn in HHcy mice significantly reduces serum homocysteine level, neuronal apoptosis and expression level of TRPM2 gene. Increased expression level of TRPM2 induced by oxidative stress might be involved in the ethiopathogenesis of HHcy related neurologic diseases.

Evaluation of TRPM (transient receptor potential melastatin) genes expressions in myocardial ischemia and reperfusion

In the present study, the expression levels of TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, and TRPM8 genes were evaluated in heart tissues after ischemia/reperfusion (IR). For this study, 30 albino male Wistar rats were equally divided into three groups as follows: Group 1: control group (n:10), Group II: ischemia group (ischemia for 60min) (n:10) and Group III: IR (reperfusion 48h after ischemia for 60min and reperfusion for 48h). The expression levels of the TRPM genes were analyzed by semi-quantitative reverse transcriptase-PCR. When compared to the ischemia control, the expression levels of TRPM2, TRPM4, and TRPM6 did not change, whereas that of TRPM7 increased. However, TRPM1, TRPM3, TRPM5, and TRPM8 were not expressed in heart tissue. Histopathological analysis of the myocardial tissues showed that the structures that were most damaged were those exposed to IR. The findings showed that there is a positive relationship between TRPM7 expression and myocardial IR injury.

Effect of Verapamil and Lidocaine on TRPM and NaV1.9 Gene Expressions in Renal Ischemia-Reperfusion

BackgroundTo determine effects on calcium and sodium channels of Ca2+ and Na+ channel blockers in the present study, expression levels of TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, and NaV1.9 genes were evaluated in kidney tissues after induced ischemia-reperfusion. Material and methodsForty albino Wistar male rats were equally divided into 4 groups as follows: group I: control group (n = 10), group II: ischemia group (60 minutes of ischemia + 48 hours of reperfusion; n = 10), group III: ischemia (60 minutes of ischemia + 48 hours of reperfusion) + calcium channel blocker (n = 8), group IV: ischemia (60 minutes of ischemia + 48 hours of reperfusion) + sodium channel blocker (n = 8). ResultsWhen compared to ischemia group expression levels of TRPM2, TRPM4, TRPM6, and NaV1.9 in Ca2+ and Na+ channel blocker groups were increased, whereas that of TRPM7 was decreased. However, expression levels of TRPM1, TRPM3, TRPM5, and TRPM8 were not determined in kidney tissue. Histologically, the Ca2+ channel blocker verapamil and the Na+ channel blocker lidocaine inhibited the cell death in kidney tissue compared to control. ConclusionOur study suggested that verapamil and lidocaine significantly reduce the degree of ischemia-reperfusion injury due to effects to TRPM and Nav1.9 genes.

The Role of TRP Channels in Oxidative Stress-induced Cell Death

The transient receptor potential (TRP) protein superfamily is a diverse group of voltage-independent calcium-permeable cation channels expressed in mammalian cells. These channels have been divided into six subfamilies, and two of them, TRPC and TRPM, have members that are widely expressed and activated by oxidative stress. TRPC3 and TRPC4 are activated by oxidants, which induce Na(+) and Ca(2+) entry into cells through mechanisms that are dependent on phospholipase C. TRPM2 is activated by oxidative stress or TNFalpha, and the mechanism involves production of ADP-ribose, which binds to an ADP-ribose binding cleft in the TRPM2 C-terminus. Treatment of HEK 293T cells expressing TRPM2 with H(2)O(2) resulted in Ca(2+) influx and increased susceptibility to cell death, whereas coexpression of the dominant negative isoform TRPM2-S suppressed H(2)O(2)-induced Ca(2+) influx, the increase in [Ca(2+)](i), and onset of apoptosis. U937-ecoR monocytic cells expressing increased levels of TRPM2 also exhibited significantly increased [Ca(2+)](i) and increased apoptosis after treatment with H(2)O(2) or TNFalpha. A dramatic increase in caspase 8, 9, 3, 7, and PARP cleavage was observed in TRPM2-expressing cells, demonstrating a downstream mechanism through which cell death is mediated. Inhibition of endogenous TRPM2 function through three approaches, depletion of TRPM2 by RNA interference, blockade of the increase in [Ca(2+)](i) through TRPM2 by calcium chelation, or expression of the dominant negative splice variant TRPM2-S protected cell viability. H(2)O(2) and amyloid beta-peptide also induced cell death in primary cultures of rat striatal cells, which endogenously express TRPM2. TRPM7 is activated by reactive oxygen species/nitrogen species, resulting in cation conductance and anoxic neuronal cell death, which is rescued by suppression of TRPM7 expression. TRPM2 and TRPM7 channels are physiologically important in oxidative stress-induced cell death.

TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage

TRPM2 is a Ca(2+)-permeable channel activated by oxidative stress or TNF-alpha, and TRPM2 activation confers susceptibility to cell death. The mechanisms were examined here in human monocytic U937-ecoR cells. This cell line expresses full-length TRPM2 (TRPM2-L) and several isoforms including a short splice variant lacking the Ca(2+)-permeable pore region (TRPM2-S), which functions as a dominant negative. Treatment with H(2)O(2), a model of oxidative stress, or TNF-alpha results in reduced cell viability. Expression of TRPM2-L and TRPM2-S was modulated by retroviral infection. U937-ecoR cells expressing increased levels of TRPM2-L were treated with H(2)O(2) or TNF-alpha, and these cells exhibited significantly increased intracellular calcium concentration ([Ca(2+)](i)), decreased viability, and increased apoptosis. A dramatic increase in cleavage of caspases-8, -9, -3, and -7 and poly(ADP-ribose)polymerase (PARP) was observed, demonstrating a downstream mechanism through which cell death is mediated. Bcl-2 levels were unchanged. Inhibition of the [Ca(2+)](i) rise with the intracellular Ca(2+) chelator BAPTA blocked caspase/PARP cleavage and cell death induced after activation of TRPM2-L, demonstrating the critical role of [Ca(2+)](i) in mediating these effects. Downregulation of endogenous TRPM2 by RNA interference or increased expression of TRPM2-S inhibited the rise in [Ca(2+)](i), enhanced cell viability, and reduced numbers of apoptotic cells after exposure to oxidative stress or TNF-alpha, demonstrating the physiological importance of TRPM2. Our data show that one mechanism through which oxidative stress or TNF-alpha mediates cell death is activation of TRPM2, resulting in increased [Ca(2+)](i), followed by caspase activation and PARP cleavage. Inhibition of TRPM2-L function by reduction in TRPM2 levels, interaction with TRPM2-S, or Ca(2+) chelation antagonizes this important cell death pathway.

Lack of Association between Enhanced TRPM-2/Clusterin Expression and Increased Apoptotic Activity in Sex-Hormone-Induced Prostatic Dysplasia of the Noble Rat

Although the functional role of TRPM-2/clusterin in the prostate remains controversial, it has been postulated that transcriptional activation of the gene is an important mechanism in castration-induced prostatic involution and perhaps is a means for prostatic cells to escape apoptotic induction. In the present study, we have measured expression levels of TRPM-2/clusterin and apoptotic activities in the prostates of castrated Noble (NBL) rats and those treated with testosterone (T) and estradiol-17beta (E2) for 16 weeks. We have previously shown that the combined sex hormone treatment (T+E2) induces dysplasia, a purported preneoplastic lesion, exclusively in the dorsolateral prostates (DLPs) of all treated rats. In the present study, we demonstrate that, as expected, castration readily induced enhanced TRPM-2/clusterin expression, which was accompanied by increased apoptotic activity in the epithelia of DLP and ventral prostate (VP). The increase in TRPM-2/clusterin expression appeared earlier and was more dramatic in the VP than in the DLP. In sharp contrast, treatment of rats with T+E2 for 16 weeks induced augmentation of TRPM-2/clusterin expression selectively in the dysplastic lesions of the DLP but not in the lesion-free VP. The enhanced expression of TRPM-2/clusterin in the dysplastic epithelium was, however, not attended by an increase in apoptotic activity within the lesion. Thus, the observed up-regulation of TRPM-2/clusterin expression in the dysplastic foci of T+E2-treated rats occurred in animals whose androgen status remained normal and, despite the increased level of expression of this gene, apoptotic activity in these lesions was unchanged from basal values measured in the DLPs of untreated rats. These findings suggest that TRPM-2/clusterin expression in dysplastic lesions was no longer repressed by androgen nor was it associated with apoptosis. We propose that overexpression of the gene is likely a phenotype of neoplastic transformation. In addition, we speculate that TRPM-2/clusterin may serve as a survival factor, which could favor accumulation of transformed cells in dysplastic foci and thus promote the carcinogenic process.

RP-8 and TRPM-2 gene expression is constitutive in rat liver and increased following galactosamine injury

The contribution of apoptosis to hepatocyte cell death after rat liver injury from the hepatotoxin galactosamine (GalN) was examined. Histologic evidence of diffuse hepatocyte apoptosis existed after GalN administration. Since apoptosis is an active form of cell death usually requiring new gene expression, it was determined whether genes associated with apoptosis were expressed following GalN liver injury. RP-8 and TRPM-2, two genes associated with apoptosis in other organs, were expressed in normal liver, and their mRNA levels increased after GalN injury. These genes were expressed in hepatocytes without any intralobular zonal gradient in expression. In contrast to GalN liver injury, RP-8 and TRPM-2 levels were unchanged during the purely proliferative response following rat partial hepatectomy. These data suggest that hepatocytes constitutively express the genetic program for apoptosis including the RP-8 and TRPM-2 genes. The ability of toxic liver injury to further stimulate expression of these genes may lead to apoptotic hepatocyte cell death.

Increased TRPM-2/clusterin mRNA levels during the time of retinal degeneration in mouse models of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a genetically and clinically heterogeneous group of human disorders that is characterized by diminished retinal function, visual cell loss, and blindness. Elevated levels of TRPM-2/clusterin mRNA, a marker for the apoptotic process, have been reported in retinas from patients with advanced stage RP. In the present study we examine TRPM-2/clusterin expression in two genetically distinct mouse models of RP, the rd (retinal degeneration) and rds (retinal degeneration slow) mice. We establish that in advanced postretinal degenerative stages of the rd mutant the retinal TRPM-2/clusterin mRNA levels are highly elevated, as is seen in the case of human RP. Examination of TRPM-2/clusterin mRNA levels in retina and whole eyes from the rd mouse and morphologically normal controls during the period of retinal degeneration (postnatal days 8-21) in the rd phenotype shows that TRPM-2/clusterin mRNA levels are elevated in the rd animal, and this increase begins just after postnatal day 10 and remains high for the remainder of the time course examined. Northern analysis of rds retina and whole eyes shows a delayed increase in TRPM-2/clusterin mRNA levels relative to the rd profile, coinciding with the known period of rds retinal degeneration (postnatal day 14 to 1 year). In each case, the onset of increased TRPM-2/clusterin mRNA levels coincides with the time of photoreceptor cell death.