AKI increases the risk of developing CKD, but the mechanisms linking AKI to CKD remain unclear. Because proximal tubule injury is the mainstay of AKI, we postulated that proximal tubule injury ...triggers features of CKD. We generated a novel mouse model to induce proximal tubule-specific adjustable injury by inducing the expression of diphtheria toxin (DT) receptor with variable prevalence in proximal tubules. Administration of high-dose DT in mice expressing the DT receptor consistently caused severe proximal tubule-specific injury associated with interstitial fibrosis and reduction of erythropoietin production. Mild proximal tubule injury from a single injection of low-dose DT triggered reversible fibrosis, whereas repeated mild injuries caused sustained interstitial fibrosis, inflammation, glomerulosclerosis, and atubular glomeruli. DT-induced proximal tubule-specific injury also triggered distal tubule injury. Furthermore, injured tubular cells cocultured with fibroblasts stimulated induction of extracellular matrix and inflammatory genes. These results support the existence of proximal-distal tubule crosstalk and crosstalk between tubular cells and fibroblasts. Overall, our data provide evidence that proximal tubule injury triggers several features of CKD and that the severity and frequency of proximal tubule injury determines the progression to CKD.
The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D₂-like dopamine receptors. However, long-term administration of antipsychotics can ...upregulate D₂ receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D₂ receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.
In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the ...reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero-Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.
The administration of aripiprazole (ARI), a dopamine partial agonist, could provoke abrupt psychotic worsening in patients with schizophrenia. We explored the relationship between this psychotic ...worsening and dopamine supersensitivity psychosis (DSP), which is a clinically vulnerable state. We conducted a retrospective investigation for 264 patients whose treatment medication was switched to ARI from other antipsychotics. We divided the patients into the DSP(+) group with a history of DSP episode(s) (N = 70) and the DSP(–) group without such a history (N = 194), and then compared the clinical factors relevant to the success or failure of the switch to ARI between them. The results revealed that patients in the DSP(+) group experienced psychotic worsening following the switch to ARI with a significant higher rate compared to the DSP(–) group (23% vs. 8%, P < 0.01). Moreover, the dosages of the drugs before the ARI introduction in the patients experiencing the psychotic worsening in the DSP (-) group were higher than those in other patients of the group. Our findings suggest that patients who receive high dosages of antipsychotic drugs form overt or covert DSP and such state is highly associated with psychotic worsening following ARI treatment.
Approximately one-third of schizophrenia patients eventually develop treatment-resistant schizophrenia (TRS). Although the time course of TRS development varies from patient to patient, the details ...of these variations have not been clarified. The present study compared the duration of time required to achieve control of the first-episode psychosis (FEP) between patients who went on to develop TRS and those who did not, in order to determine whether a bifurcation point exists for the transition to TRS.
The present study included 271 schizophrenia patients. Based on the clinical assessment, each patient was assigned to a TRS (n = 79) or Non-TRS group (n = 182). Clinical factors relating to FEP treatment such as the duration of initial hospital admission and the degree of improvement were retrospectively identified.
There was no significant difference in the duration of initial hospital admission (defined as the time from treatment introduction to successful discharge) between the two groups (mean of 87.9 days for TRS vs. 53.3 days for Non-TRS). The degree of improvement during initial hospital admission of the TRS group was significantly lower than that of the Non-TRS group (Global Assessment of Functioning (GAF) of 50 points for TRS vs. 61 points for Non-TRS). Approximately half of the TRS patients showed an acute onset pattern and longer hospital admission (mean 169 days) for their FEP. The other half of TRS patients needed no hospital admission, indicating an insidious onset pattern with no clear psychotic episode and treatment introduction without hospital admission.
Future TRS patients can have difficulty in improvement during their FEP. There appear to be two distinct patterns for the development of TRS. One pattern is characterized by refractory positive symptoms and a longer period to control the first psychosis; the other shows latent or insidious onset and poor response to the initial treatment.
A significant portion of patients with schizophrenia who respond to initial antipsychotic treatment acquire treatment resistance. One of the possible pathogeneses of treatment-resistant schizophrenia ...(TRS) is antipsychotic-induced dopamine supersensitivity psychosis (Ai-DSP). Patients with this disease progression might share some genetic vulnerabilities, and thus determining individuals with higher risks of developing Ai-DSP could contribute to preventing iatrogenic development of TRS. Therefore, we decided to examine whether combinations of functional single nucleotide polymorphisms (SNPs) known to affect dopaminergic functions are related to Ai-DSP development.
In this case-control study, 357 Japanese participants diagnosed with schizophrenia or schizoaffective disorder were recruited and divided into two groups, those with and without Ai-DSP. As functional SNPs, we examined rs10770141 of the tyrosine hydroxylase gene, rs4680 of the catechol-O-methyltransferase gene, and rs1799732 and rs1800497 of the DRD2 genes, which are known to possess strong directional ties to dopamine synthesis, dopamine degradation and post-synaptic DRD2 prevalence, respectively.
Among the 357 Japanese patients with schizophrenia or schizoaffective disorder, 130 were classified as Ai-DSP(+) and the other 227 as Ai-DSP(-). Significantly higher proportions of Ai-DSP(+) patients were found to have the SNP combinations of rs10770141/rs4680 (57.9%, OR2.654, 95%CI1.036-6.787, P = 0.048) and rs10770141/rs4680/ rs1800497 (64.3%, OR4.230, 95%CI1.306-13.619, P = 0.029). However, no single SNP was associated with Ai-DSP.
We preliminarily found that carrying particular combinations of functional SNPs, which are related to relatively higher dopamine synthesis and dopamine degradation and lower naïve DRD2, might indicate vulnerability to development of Ai-DSP. However, further studies are needed to validate the present results.
Abstract Background Although a variety of factors are known to be significantly related to poor prognosis in schizophrenia, their interactions remain unclear. Dopamine supersensitivity psychosis ...(DSP) is a clinical concept related to long-term pharmacotherapy and could be one of the key factors contributing to the development of treatment-resistant schizophrenia (TRS). The present study aims to explore the effect of DSP on progression to TRS. Methods Two-hundreds and sixty-five patients were classified into either a TRS or Non-TRS group based on retrospective survey and direct interview. The key factors related to prognosis, including the presence or absence of DSP episodes, were extracted, and each factor was compared between the two groups. Results All parameters except for the duration of untreated psychosis (DUP) were significantly worse in the TRS group compared to the Non-TRS group. In particular, the TRS group presented with a significantly higher rate of DSP episodes than the Non-TRS group. Regression analysis supported the notion that DSP plays a pivotal role in the development of TRS. In addition, deficit syndrome was suggested to be a diagnostic subcategory of TRS. Conclusions Our data confirmed that the key predicting factors of poor prognosis which have been established would actually affect somehow the development of TRS. In addition, the occurrence of a DSP episode during pharmacotherapy was shown to promote treatment refractoriness.
It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated ...that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06–1.45,
p
< 0.001) for rs4680, 1.73 (95% CI 1.47–2.02,
p
< 0.0001) for rs1800497, and 1.79 (95% CI 1.35–2.36,
p
< 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (
p
< 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59–2.19,
p
< 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.
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