Role of ADAM17 in kidney disease Palau, Vanesa; Pascual, Julio; Soler, Maria José ...
American journal of physiology. Renal physiology,
08/2019, Letnik:
317, Številka:
2
Journal Article
Recenzirano
Odprti dostop
It is known that the renin-angiotensin system plays a major role in the pathophysiology of cardiovascular disease and renal injury. Within the renin-angiotensin system, angiotensin-converting enzyme ...2 (ACE2) cleaves ANG II to generate ANG(1-7) peptide, which counteracts the adverse effects of ANG II accumulation. ACE2 can undergo cleavage or shedding to release the catalytically active ectodomain into the circulation by a disintegrin and metalloprotease (ADAM)17, also known as TNF-α-converting enzyme. ADAM17 is involved in many pathological processes such as cancer, inflammatory diseases, neurological diseases, cardiovascular diseases, atherosclerosis, diabetes, and hypertension. Clinical and experimental studies have shown that ADAM17 is involved in chronic kidney disease (CKD) with a proinflammatory and profibrotic role, suggesting that it could be an important mediator of CKD progression. ADAM17 inhibition attenuates fibrosis and inflammation, suggesting that its inhibition may be a possible new valuable therapeutic tool in fibrotic kidney disease treatment. In addition, in renal disease, some experimental studies have demonstrated that ADAM17 is differently expressed in the kidney. Thus, ADAM17 is highly expressed in distal renal tubules and increased in the whole kidney in diabetic models. In this article, we will review the role of ADAM17 under physiological and pathological conditions. We will mainly focus on the importance of ADAM17 in the context of CKD.
Revisiting Experimental Models of Diabetic Nephropathy Giralt-López, Anna; Molina-Van den Bosch, Mireia; Vergara, Ander ...
International journal of molecular sciences,
05/2020, Letnik:
21, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the prevalence of diabetic nephropathy (DN) has also increased, becoming the ...main cause of end-stage renal disease (ESRD) in the developed world. DN is characterized by albuminuria, a decline in glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, glomerular basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances in the last years have been able to modify and delay the natural course of diabetic kidney disease (DKD). Nevertheless, there is still an urgent need to characterize the pathways that are involved in DN, identify risk biomarkers and prevent kidney failure in diabetic patients. Rodent models provide valuable information regarding how DN is set and its progression through time. Despite the utility of these models, kidney disease progression depends on the diabetes induction method and susceptibility to diabetes of each experimental strain. The classical DN murine models (Streptozotocin-induced, Akita, or obese type 2 models) do not develop all of the typical DN features. For this reason, many models have been crossed to a susceptible genetic background. Knockout and transgenic strains have also been created to generate more robust models. In this review, we will focus on the description of the new DN rodent models and, additionally, we will provide an overview of the available methods for renal phenotyping.
Endothelin Receptor Antagonists in Kidney Disease Martínez-Díaz, Irene; Martos, Nerea; Llorens-Cebrià, Carmen ...
International journal of molecular sciences,
02/2023, Letnik:
24, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the ...endothelin receptor type A (ET
) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ET
receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.
Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney ...disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.
ADAM17 is a disintegrin and metalloproteinase capable of cleaving the ectodomains of a diverse variety of molecules including TNF-α, TGF-α, L-selectin, and ACE2. We have previously demonstrated that ...renal ADAM17 is upregulated in diabetic mice. The role of endothelial (eAdam17) and proximal tubular (tAdam17) Adam17 deletion in renal histology, modulation of the renin angiotensin system (RAS), renal inflammation, and fibrosis was studied in a mouse model of type 1 Diabetes Mellitus. Moreover, the effect of Adam17 deletion in an in vitro 3D cell culture from human proximal tubular cells under high glucose conditions was evaluated. eAdam17 deletion attenuates renal fibrosis and inflammation, whereas tAdam17 deletion decreases podocyte loss, attenuates the RAS, and decreases macrophage infiltration, α-SMA and collagen accumulation. The 3D in vitro cell culture reinforced the findings obtained in tAdam17KO mice with decreased fibrosis in the Adam17 knockout spheroids. In conclusion, Adam17 deletion either in the endothelial or the tubular cells mitigates kidney injury in the diabetic mice by targeting different pathways. The manipulation of Adam17 should be considered as a therapeutic strategy for treating DN.
RAS and sex differences in diabetic nephropathy Clotet, Sergi; Riera, Marta; Pascual, Julio ...
American journal of physiology. Renal physiology,
05/2016, Letnik:
310, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The incidence and progression of kidney diseases are influenced by sex. The renin-angiotensin system (RAS) is an important regulator of cardiovascular and renal function. Sex differences in the renal ...response to RAS blockade have been demonstrated. Circulating and renal RAS has been shown to be altered in type 1 and type 2 diabetes; this enzymatic cascade plays a critical role in the development of diabetic nephropathy (DN). Angiotensin converting enzyme (ACE) and ACE2 are differentially regulated depending on its localization within the diabetic kidney. Furthermore, clinical and experimental studies have shown that circulating levels of sex hormones are clearly modulated in the context of diabetes, suggesting that sex-dependent RAS regulation may be also be affected in these individuals. The effect of sex hormones on circulating and renal RAS may be involved in the sex differences observed in DN progression. In this paper we will review the influence of sex hormones on RAS expression and its relation to diabetic kidney disease. A better understanding of the sex dimorphism on RAS might provide a new approach for diabetic kidney disease treatment.
Abstract
The clinical spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic infection to severe pneumonia with respiratory failure and even death. More severe cases with ...higher mortality have been reported in older patients and in those with chronic illness such as hypertension, diabetes or cardiovascular diseases. In this regard, patients with chronic kidney disease (CKD) have a higher rate of all-type infections and cardiovascular disease than the general population. A markedly altered immune system and immunosuppressed state may predispose CKD patients to infectious complications. Likewise, they have a state of chronic systemic inflammation that may increase their morbidity and mortality. In this review we discuss the chronic immunologic changes observed in CKD patients, the risk of COVID-19 infections and the clinical implications for and specific COVID-19 therapy in CKD patients. Indeed, the risk for severe COVID-19 is 3-fold higher in CKD than in non-CKD patients; CKD is 12-fold more frequent in intensive care unit than in non-hospitalized COVID-19 patients, and this ratio is higher than for diabetes or cardiovascular disease; and acute COVID-19 mortality is 15–25% for haemodialysis patients even when not developing pneumonia.
Obesity is one of the epidemics of our era. Its prevalence is higher than 30% in the U.S. and it is estimated to increase by 50% in 2030. Obesity is associated with a higher risk of all-cause ...mortality and it is known to be a cause of chronic kidney disease (CKD). Typically, obesity-related glomerulopathy (ORG) is ascribed to renal hemodynamic changes that lead to hyperfiltration, albuminuria and, finally, impairment in glomerular filtration rate due to glomerulosclerosis. Though not only hemodynamics are responsible for ORG: adipokines could cause local effects on mesangial and tubular cells and podocytes promoting maladaptive responses to hyperfiltration. Furthermore, hypertension and type 2 diabetes mellitus, two conditions generally associated with obesity, are both amplifiers of obesity injury in the renal parenchyma, as well as complications of overweight. As in the native kidney, obesity is also related to worse outcomes in kidney transplantation. Despite its impact in CKD and cardiovascular morbility and mortality, therapeutic strategies to fight against obesity-related CKD were limited for decades to renin-angiotensin blockade and bariatric surgery for patients who accomplished very restrictive criteria. Last years, different drugs have been approved or are under study for the treatment of obesity. Glucagon-like peptide-1 receptor agonists are promising in obesity-related CKD since they have shown benefits in terms of losing weight in obese patients, as well as preventing the onset of macroalbuminuria and slowing the decline of eGFR in type 2 diabetes. These new families of glucose-lowering drugs are a new frontier to be crossed by nephrologists to stop obesity-related CKD progression.
Cryopreservation has adverse effects on the post‐thaw sperm quality due to oxidative stress and the presence of bacteria. To minimize such effects, plant extracts have been included in the ...composition of the semen diluents. The objective of the present study was to evaluate the antimicrobial and antioxidant effects of Moringa oleifera seed extract (MOSE) on cryopreserved ram semen, as well as its impact on in vitro fertilization. Semen from six hair rams was treated with five treatments before cryopreservation: Control (without any antibiotic), Standard (conventional antibiotic), 1.0, 10.0, and 50.0 mg/ml of MOSE. Post‐thawing sperm characteristics were evaluated by the computer‐assisted semen analysis. Antimicrobial activity was assessed by counting colony‐forming units (CFU) and the antioxidant capacity by the ferric reducing antioxidant power method. A heterologous in vitro fertilization technique was implemented to measure the fertilization rate. Progressive and rapid motility, membrane and acrosome integrity, and active mitochondria were higher (p < .05) in the 10.0 mg/ml treatment compared with Standard after thawing. All M. oleifera treatments showed inhibition of CFU. The antioxidant capacity of M. oleifera seed extract was higher in the 10.0 and 50.0 mg/ml treatments. Fertilization rate (cleavage percentage) was higher (p < .05) in the 10.0 mg/ml (82.9 ± 10.0) and Control (82.5 ± 9.9) treatments compared with Standard (73.7 ± 9.1). The addition of 10.0 mg/ml of MOSE to ram semen inhibits the development of microorganisms and improves sperm characteristics and the in vitro fertility of the semen.
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