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1.
Am J Physiol Renal Physiol ; 327(3): F412-F425, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38961845

RESUMO

There are diverse pathophysiological mechanisms involved in acute kidney injury (AKI). Among them, overactivity of the renin-angiotensin system (RAS) has been described. Angiotensin-converting enzyme 2 (ACE2) is a tissue RAS enzyme expressed in the apical border of proximal tubules. Given the important role of ACE2 in the metabolism of angiotensin II, this study aimed to characterize kidney and urinary ACE2 in a mouse model of AKI. Ischemia-reperfusion injury (IRI) was induced in C57BL/6 mice by clamping of the left renal artery followed by removal of the right kidney. In kidneys harvested 48 h after IRI, immunostaining revealed a striking maldistribution of ACE2 including spillage into the tubular lumen and the presence of ACE2-positive luminal casts in the medulla. In cortical membranes, ACE2 protein and enzymatic activity were both markedly reduced (37 ± 4 vs. 100 ± 6 ACE2/ß-actin, P = 0.0004, and 96 ± 14 vs. 152 ± 6 RFU/µg protein/h, P = 0.006). In urine, full-length membrane-bound ACE2 protein (100 kDa) was markedly increased (1,120 ± 405 vs. 100 ± 46 ACE2/µg creatinine, P = 0.04), and casts stained for ACE2 were recovered in the urine sediment. In conclusion, in AKI caused by IRI, there is a marked loss of ACE2 from the apical tubular border with deposition of ACE2-positive material in the medulla and increased urinary excretion of full-length membrane-bound ACE2 protein. The deficiency of tubular ACE2 in AKI suggests that provision of this enzyme could have therapeutic applications and that its excretion in the urine may also serve as a diagnostic marker of severe proximal tubular injury.NEW & NOTEWORTHY This study provides novel insights into the distribution of kidney ACE2 in a model of AKI by IRI showing a striking detachment of apical ACE2 from proximal tubules and its loss in urine and urine sediment. The observed deficiency of kidney ACE2 protein and enzymatic activity in severe AKI suggests that administration of forms of this enzyme may mitigate AKI and that urinary ACE2 may serve as a potential biomarker for tubular injury.


Assuntos
Injúria Renal Aguda , Enzima de Conversão de Angiotensina 2 , Rim , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Injúria Renal Aguda/urina , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/enzimologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/urina , Biomarcadores/urina , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Rim/enzimologia , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/urina , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , Traumatismo por Reperfusão/urina , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/enzimologia
2.
BMC Nephrol ; 22(1): 299, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-34481475

RESUMO

BACKGROUND: We tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1. METHODS: At birth (P0), neonatal rat pups were exposed to brief IH episodes from the first day of life (P0) to P7 or from P0-P14. Pups were either euthanized immediately or placed in room air (RA) until P21. RA littermates served as controls. Kidneys were harvested at P7, P14, and P21 for histopathology; angiotensin converting enzyme (ACE), ACE-2, ET-1, big ET-1, and malondialdehyde (MDA) levels; immunoreactivity of ACE, ACE-2, ET-1, ET-2, ET receptors (ETAR, ETBR), and hypoxia inducible factor (HIF)1α; and apoptosis (TUNEL stain). RESULTS: Histopathology showed increased renal damage with 8-12 IH episodes/day, and was associated with Ang II, ACE, HIF1α, and apoptosis. ACE-2 was not expressed at P7, and minimally increased at P14. However, a robust ACE-2 response was seen during recovery with maximum levels noted in the groups recovering from 8 IH episodes/day. ET-1, big ET-1, ETAR, ETBR, and MDA increased with increasing levels of neonatal IH. CONCLUSIONS: Chronic neonatal IH causes severe damage to the developing kidney with associated elevations in vasoconstrictors, suggesting hypertension, particularly with 8 neonatal IH episodes. ACE-2 is not activated in early postnatal life, and this may contribute to IH-induced vasoconstriction. Therapeutic targeting of ACE and ET-1 may help decrease the risk for kidney injury in the developing neonate to prevent and/or treat neonatal acute kidney injury and/or chronic kidney disease.


Assuntos
Injúria Renal Aguda/etiologia , Biomarcadores/urina , Hipóxia/complicações , Rim/patologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/urina , Enzima de Conversão de Angiotensina 2/urina , Animais , Animais Recém-Nascidos , Apoptose , Estresse Oxidativo , Peptidil Dipeptidase A/urina , Ratos , Ratos Sprague-Dawley
4.
FASEB J ; 35(8): e21745, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34191346

RESUMO

Studies are needed to identify useful biomarkers to assess the severity and prognosis of COVID-19 disease, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus. Here, we examine the levels of various plasma species of the SARS-CoV-2 host receptor, the angiotensin-converting enzyme 2 (ACE2), in patients at different phases of the infection. Human plasma ACE2 species were characterized by immunoprecipitation and western blotting employing antibodies against the ectodomain and the C-terminal domain, using a recombinant human ACE2 protein as control. In addition, changes in the cleaved and full-length ACE2 species were also examined in serum samples derived from humanized K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2. ACE2 immunoreactivity was present in human plasma as several molecular mass species that probably comprise truncated (70 and 75 kDa) and full-length forms (95, 100, 130, and 170 kDa). COVID-19 patients in the acute phase of infection (n = 46) had significantly decreased levels of ACE2 full-length species, while a truncated 70-kDa form was marginally higher compared with non-disease controls (n = 26). Levels of ACE2 full-length species were in the normal range in patients after a recovery period with an interval of 58-70 days (n = 29), while the 70-kDa species decreased. Levels of the truncated ACE2 species served to discriminate between individuals infected by SARS-CoV-2 and those infected with influenza A virus (n = 17). In conclusion, specific plasma ACE2 species are altered in patients with COVID-19 and these changes normalize during the recovery phase. Alterations in ACE2 species following SARS-CoV-2 infection warrant further investigation regarding their potential usefulness as biomarkers for the disease process and to asses efficacy during vaccination.


Assuntos
Enzima de Conversão de Angiotensina 2/sangue , COVID-19/sangue , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/líquido cefalorraquidiano , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/urina , Biomarcadores/sangue , Química Encefálica , Colo/química , Feminino , Humanos , Fígado/química , Masculino , Pessoa de Meia-Idade , Saliva/química
5.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922918

RESUMO

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.


Assuntos
COVID-19/patologia , Hiperandrogenismo/patologia , Síndrome do Ovário Policístico/patologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/sangue , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/urina , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , COVID-19/complicações , COVID-19/virologia , Catepsina L/genética , Catepsina L/metabolismo , Di-Hidrotestosterona/farmacologia , Feminino , Humanos , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/complicações , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Regulação para Cima/efeitos dos fármacos , Internalização do Vírus
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