scholarly journals Proteolytic Cleavage by Matriptase Exacerbating Kidney Injury: a Novel Therapeutic Target

2019 ◽  
Author(s):  
Shota Ozawa ◽  
Masaya Matsubayashi ◽  
Hitoki Nanaura ◽  
Motoko Yanagita ◽  
Kiyoshi Mori ◽  
...  

AbstractChronic kidney disease (CKD) is a progressive disease, and podocyte injury is a potential mechanism. We found that Matriptase was activated at podocytes in CKD patients and mice while a Matriptase inhibitor slowed the progression of mouse kidney disease. The mechanism could be accounted for by an imbalance favoring Matriptase over its cognate inhibitor, hepatocyte growth factor activator inhibitor type 1 (HAI-1), as conditional depletion of HAI-1 in podocytes accelerates podocyte injury. Intriguingly, the N-terminal of Podocin (Podocin-N), as a consequence of Matriptase cleavage of Podocin, translocates to nucleoli. These results suggest that aberrant activation of Matriptase would cause podocyte injury, and a targeting Matriptase could be a novel therapeutic strategy for CKD patients.Significant statementChronic kidney disease (CKD) is a progressive disease. If podocytes, which are specialized cells of the kidney glomerulus that wrap around capillaries, are injured, kidney injury is exacerbated. Thus, a therapeutic strategy to addressing CKD would be to block podocyte injury. The present study provides evidence that Matriptase cleaves Podocin, a component of podocyte slit membrane, and the N-terminal of podocin translocates to nucleoli, causing kidney injury. Our findings show that the N-terminal of Podocin plays an efficient role for cell fate in podocytes. In addition, the inhibition of Matriptase would be a potential therapeutic target for CKD.

2017 ◽  
Vol 313 (4) ◽  
pp. F835-F841 ◽  
Author(s):  
Cierra N. Sharp ◽  
Leah J. Siskind

Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury.


2019 ◽  
Vol 95 (1) ◽  
pp. 123-137 ◽  
Author(s):  
Hiroaki Kikuchi ◽  
Emi Sasaki ◽  
Naohiro Nomura ◽  
Takayasu Mori ◽  
Yoji Andrew Minamishima ◽  
...  

2010 ◽  
Vol 120 (1-2) ◽  
pp. 54-58
Author(s):  
Piotr Wesołowski ◽  
Marek Saracyn ◽  
Zbigniew Nowak ◽  
Zofia Wańkowicz

Author(s):  
John R. Prowle ◽  
Lui G. Forni ◽  
Max Bell ◽  
Michelle S. Chew ◽  
Mark Edwards ◽  
...  

AbstractPostoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.


2021 ◽  
Vol 22 (14) ◽  
pp. 7642
Author(s):  
Zoran V. Popovic ◽  
Felix Bestvater ◽  
Damir Krunic ◽  
Bernhard K. Krämer ◽  
Raoul Bergner ◽  
...  

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Feyza Bora ◽  
Emine Asar ◽  
Fatih Yılmaz ◽  
Ümit Çakmak ◽  
Fevzi F Ersoy ◽  
...  

Abstract Background and Aims It is evident that Chronic Kidney Disease (CKD) influences the risk of developing AKI (Acute Kidney Injury) and recent studies suggest that CKD patients who experienced an episode of AKI are more likely to progress to end stage renal disease (ESRD) than patients without CKD. AKI-CKD association might originate from common comorbidities associated with both AKI and CKD, such as diabetes and/or hypertension, and concurrent increase in interventions leading to frequent exposure to various nephrotoxins. AKI in the elderly has been shown to increase the risk of progression to CKD to ESRD. AKI is common in critically ill patients, and those patients with the most severe form of AKI, requiring RRT, have a mortality rate of 50–80 %. Patients with an eGFR &lt;45 ml/min per 1.73m2 who experienced an episode of dialysis-requiring AKI were at very high risk for impaired recovery of renal function. Our aim was to determine the reasons that initiate hemodialysis (renal decompensation) in patients with regular follow-up in the low clearance polyclinic without renal replacement treatment (RRT). Method The retrospective study included predialysis CKD patients who had followed up regularly and had undergone RRT in recent 4 years. Data on baseline characteristics and medical history were obtained from patient hospital records. Results Of the 228 patients, 155 (68%) were male and 73 (32%) were female. The mean age was 58 years (45-66). Diabetes Mellitus was the first in the etiology of CKD (26,3 %), the second was unknown (12,7 %), the third was hypertension (11,8 %). 145 patients (63,6%) underwent regular hemodialysis (HD) (62 years, 55-69), 25 patients (11%) began peritoneal dialysis (PD), 58 patients (25%) had renal transplantation. 52 patients underwent HD with renal decompensation, 22 (%42,3) had working arteriovenous fistula (AVF). There was no decompensation in patients with PD or transplantation plan. 34 patients started HD because of infections (65%), 8 patients (15%) after operations (4 was Coronary Artery Bypass Grafting-CABG), 6 patients (%11,5) after coronary angiography, 4 patients (7,5%) with cardiac decompensation. 2 patients died during the hospitalisation for infections. Of 145 HD patients, 89 (%61,4) had AVF. The patients who had renal decompensation were more older 63 (58-70), have lower Hgb 9,7 g/L (9,1-10,7) and albumin 3,5 g/L (3,2-3,9) level (p&lt;0,05). There was no difference in eGFR at the beginning of HD between renal decompensation and other HD patients. 42 patients did not undergo HD at the time we suggested during visits. Of them 9 patients (%21) had renal decompensation (6 infections,3 CABG), 17 patients (%40) had AVF. 3 of them died. The others underwent HD for uremic complications. Conclusion We have shown that infections are as the leading cause of renal decompensation. Most of our patients who started to RRT from our low clearance outpatient clinic have chosen HD for RRT. Prevention of infections via vaccination programs or early diagnosis at regular policlinic or telephone visits, and informing patients adequately about nephrotoxic drugs or the conditions that may cause renal decompensation are among the first tasks of the predialysis outpatient clinic. Transition of CKD patients to RRTs, with proper preparation, neither late nor early- at the most appropriate time- should be among in our goals. This may reduce the cost of ESRD patients.


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