The role of TRPC6 in kidney damage

Acute kidney injury (AKI) and chronic kidney disease (CKD) are worldwide common cause of death, strongly increases the risk of cardiovascular disease, and associated with a substantial economic burden. Severe AKI can progress to CKD. CKD is commonly the consequence of diabetes, high blood pressure, or glomerulonephritis, which initiate kidney injury that results in a period of months or years to inflammation, fibrosis, and ultimately to nephron loss. The initiation and progression of kidney fibrosis appear to involve a complex, so far incompletely characterized interaction between injured tubules, fibroblasts, pericytes, endothelial cells and inflammatory cells. During past years, novel drug targets such as the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) emerged, as it was associated with focal segmental glomerulosclerosis. However, the function of TRPC6 channel in kidney injury is still unknown. Moreover, the effectiveness a novel selective TRPC6 inhibitor (larixyl N-methylcarbamate, SH045) has not been studied in animal models of the human disease such as the ischemia reperfusion injury (IRI) or the unilateral urethra obstruction (UUO) model. We used Trpc6-/- mice and SH045 to evaluate short-term outcomes of ischemia reperfusion injury (IRI)-induced AKI. Our results demonstrated that neither Trpc6 deficiency nor pharmacological inhibition of TRPC6 influences the short-term outcomes in AKI. These findings improve the understanding of the role of TRPC6 in acute kidney damage. We also used the inbred New Zealand Obese (NZO) mouse strain better mimicking human metabolic syndrome and CKD pathophysiology to model subchronic kidney injury. This type of kidney injury was induced by unilateral urethra obstruction (UUO). As opposed to AKI, SH045 ameliorated renal inflammation and fibrogenesis in UUO mouse model. The renal expression of the pro-fibrotic markers and chemokines were markedly decreased by SH045 treatment. Furthermore, renal immune cells infiltration and tubulointerstitial fibrosis were decreased in SH045 treated NZO-UUO mice. We conclude that TRPC6 pharmacological inhibition (SH045) is a promising antifibrotic strategy to treat progressive tubulo-interstitial fibrosis.Akute Nierenschädigung (AKI) and chronische Nierenerkrankung (CKD) sind weltweit eine häufige Todesursache, erhöhen das Risiko von Herz-Kreislauf-Erkrankungen stark und sind mit einer erheblichen wirtschaftlichen Belastung verbunden. Eine schwere AKI kann zu einer CNI führen. CKD ist in der Regel die Folge von Diabetes, Bluthochdruck oder Glomerulonephritis, die eine Nierenschädigung auslösen, die über Monate oder Jahre hinweg zu Entzündungen, Fibrose und schließlich zum Verlust von Nephronen führt. Der Anfang und Fortschreiten der Nierenfibrose scheint eine komplexe, bisher unvollständig charakterisierte Wechselwirkung zwischen verletzten Tubuli, Fibroblasten, Perizyten, Endothelzellen und Entzündungszellen zu sein. In den vergangenen Jahren wurden neue Wirkstoffziele wie der transiente Rezeptorpotential-Kationenkanal, Unterfamilie C, Mitglied 6 (TRPC6) entdeckt, der mit fokalen segmentalen Glomerulosklerose assoziiert wurde. Die Funktion des TRPC6-Kanals bei Nierenverletzungen ist jedoch noch unbekannt. Darüber hinaus wurde die Wirksamkeit eines neuartigen selektiven TRPC6-Inhibitors (Larixyl-N-Methylcarbamat, SH045) in Tiermodellen der menschlichen Erkrankung, wie der Ischämie-Reperfusionsverletzung (IRI) oder dem Modell der einseitigen Harnröhrenobstruktion (UUO), nicht untersucht. Wir verwendeten Trpc6-/- Mäuse und SH045, um kurzfristige Folgen durch Ischämie-Reperfusionsverletzung (IRI)-induzierte AKI festzustellen. Unsere Ergebnisse zeigten, dass weder TRPC6-Mangel noch pharmakologische Hemmung von TRPC6 die kurzfristigen Folgen der AKI beeinflussen. Diese Ergebnisse verbessern das Verständnis der Rolle von TRPC6 bei akuten Nierenschäden. In der UUO-Studie verwendeten wir den neuseeländischen fettleibigen (NZO) Mausstamm, der das humane metabolische Syndrom und die CKD-Pathophysiologie besser imitiert. Im Gegensatz zu AKI verbesserte SH045 die Nierenentzündung und Fibrogenese im UUO-Mausmodell. Die renale Expression von pro-fibrotischen Markern und Chemokine wurde durch die SH045-Behandlung deutlich verringert. Darüber hinaus waren die Infiltration von renalen Immunzellen und die tubulointerstitielle Fibrose bei den mit SH045 behandelten NZO-UUO-Mäusen verringert. Wir schließen daraus, dass die pharmakologische Hemmung von TRPC6 (SH045) eine vielversprechende antifibrotische Strategie zur Behandlung der progressiven tubulo-interstitiellen Fibrose darstellt

Quantum Image Processing and Its Application to Edge Detection: Theory and Experiment

Processing of digital images is continuously gaining in volume and relevance, with concomitant demands on data storage, transmission and processing power. Encoding the image information in quantum-mechanical systems instead of classical ones and replacing classical with quantum information processing may alleviate some of these challenges. By encoding and processing the image information in quantum-mechanical systems, we here demonstrate the framework of quantum image processing, where a pure quantum state encodes the image information: we encode the pixel values in the probability amplitudes and the pixel positions in the computational basis states. Our quantum image representation reduces the required number of qubits compared to existing implementations, and we present image processing algorithms that provide exponential speed-up over their classical counterparts. For the commonly used task of detecting the edge of an image, we propose and implement a quantum algorithm that completes the task with only one single-qubit operation, independent of the size of the image. This demonstrates the potential of quantum image processing for highly efficient image and video processing in the big data era.Comment: 13 pages, including 9 figures and 5 appendixe

Proinflammatory Effect of High Glucose Concentrations on HMrSV5 Cells via the Autocrine Effect of HMGB1

Background: Peritoneal fibrosis, in which inflammation and apoptosis play crucial pathogenic roles, is a severe complication associated with the treatment of kidney failure with peritoneal dialysis (PD) using a glucose-based dialysate. Mesothelial cells (MCs) take part in the inflammatory processes by producing various cytokines and chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8). The apoptosis of MCs induced by high glucose levels also contributes to complications of PD. High mobility group protein B1 (HMGB1) is an inflammatory factor that has repeatedly been proven to be related to the occurrence of peritoneal dysfunction.Aim: In this study, we aimed to explore the effect and underlying mechanism of endogenous HMGB1 in high-glucose-induced MC injury.Methods: The human peritoneal MC line, HMrSV5 was cultured in high-glucose medium and incubated with recombinant HMGB1. Cellular expression of HMGB1 was blocked using HMGB1 small interfering RNA (siRNA). Apoptosis and production of inflammatory factors as well as the potential intermediary signaling pathways were examined.Results: The major findings of these analyses were: (1) MCs secreted HMGB1 from the nucleus during exposure to high glucose levels; HMGB1 acted in an autocrine fashion on the MCs to promote the production of MCP-1 and IL-8; (2) HMGB1 had little effect on high-glucose-induced apoptosis of the MCs; and (3) HMGB1-mediated MCP-1 and IL-8 production depended on the activation of MAPK signaling pathways. In conclusion, endogenous HMGB1 plays an important role in the inflammatory reaction induced by high glucose on MCs via mitogen-activated protein kinase (MAPK) signaling pathways, but it seems to have little effect on high-glucose-induced apoptosis

In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1a1, Col3a1, Col4a1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and -smooth muscle actin (-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome

In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1a1, Col3a1, Col4a1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and -smooth muscle actin (-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome

In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1a1, Col3a1, Col4a1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and -smooth muscle actin (-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome