Nephrotic syndrome is a disorder of the glomerular filtration barrier, and central to the filtration mechanism of the glomerular filtration barrier is the podocyte. We are starting to better understand how this cell, with its unique architectural features, fulfils its exact filtration properties. The multiprotein complex between adjacent podocyte foot processes, the slit diaphragm, is essential to the control of the actin cytoskeleton and cell morphology. Many of the proteins within the slit diaphragm, including nephrin, podocin, transient receptor potential-6 channel, and alpha-actinin-4, have been identified via genetic studies of inherited nephrotic syndromes. Signaling from slit diaphragm proteins to the actin cytoskeleton is mediated via the Rho GTPases. These are thought to be involved in the control of podocyte motility, which has been postulated as a focus of proteinuric pathways. Nephrotic syndrome is currently treated with immunosuppressive therapy, with significant adverse effects. These therapies may work in nephrotic syndrome due to specific effects on the podocytes. This review aims to describe our current understanding of the cellular pathways and molecules within the podocyte relevant to nephrotic syndrome and its treatment. With our current knowledge of the cellular biology of the podocyte, there is much hope for targeted therapies for nephrotic syndromes.
Actin Cytoskeleton ; Diaphragm ; Filtration ; Foot ; Glomerular Filtration Barrier ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Nephrotic Syndrome ; Podocytes ; Proteins ; Proteinuria ; rho GTP-Binding Proteins

Objective: To compare the time and spatial distribution of hepatitis C and HIV/AIDS cases and its correlation, in China from 2012 to 2017. Methods: Data on reported hepatitis C and HIV/AIDS cases was gathered from the Direct Reporting System of Infectious Diseases Information Network in China, 2012 to 2017 while annually collected provincial data was based on the date of review and current address. Correlation of the data was analyzed, using both simple correlation and linear regression methods. Results: The number of reported cases of hepatitis C remained stable in China, in 2012-2017, with the number of annual reported cases as 201 622, 203 155, 202 803, 207 897, 206 832 and 214 023, respectively. The number of reported cases on HIV/AIDS showed a steady growing trend, from 82 434, 90 119, 103 501, 115 465, 124 555 to 134 512. However, the numbers of hepatitis C and HIV/AIDS cases were in the same, top six provinces: Henan, Guangdong, Xinjiang, Guangxi, Hunan and Yunnan. Results from the simple correlation analysis indicated that there was a positive correlation (r>0.5, P<0.01) existed between the above-said two kinds of cases at the provincial level in China, in 2012-2017. Again, results from the linear regression analysis also showed that the correlation coefficient r(s) and year was strongly correlated (r=0.966) while r(s) had been linearly increasing with time. Conclusions: Our data showed that there were temporal and spatial correlations existed between the reported cases of hepatitis C and HIV/AIDS at the provincial level, suggesting that relevant prevention and control programs be carried out in areas with serious epidemics. Combination of the two strategies should be encouraged, especially on prevention and treatment measures related to blood transmission.
Age Distribution ; China/epidemiology* ; Epidemics ; HIV ; HIV Infections/ethnology* ; Hepatitis C/ethnology* ; Humans ; Linear Models ; Spatial Analysis ; Spatio-Temporal Analysis ; Young Adult

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.

Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.