Sinkkihomeostaasin geeniperheistä ZNT ja ZIP. Perhe ZNT, 10 jäsentä.

Kaksi proteiiniperhettä SLC30A (ZNT) ja SLC39A (ZIP) osallistuvat sinkin homeostaasiin.Sinkillä on merkitys glukoosiaineenvaihdunnalle.
https://pubmed.ncbi.nlm.nih.gov/29372370/?from_term=SLC30A+family&from_pos=1

ZNT geeni perhe

(1) Zinc Transporter 1, SLC30, ZNT(1q32.3)

Sinkinpuute tyyppi. Acrodermatitis enteropathica.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A1&keywords=ZNT1 GeneCards Summary for SLC30A1 Gene

SLC30A1 (Solute Carrier Family 30 Member 1) is a Protein Coding gene. Diseases associated with SLC30A1 include Epidermodysplasia Verruciformis 1 and Acrodermatitis Enteropathica, Zinc-Deficiency Type. Among its related pathways are Mineral absorption and Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and calcium channel inhibitor activity. An important paralog of this gene is SLC30A10. UniProtKB/Swiss-Prot Summary for SLC30A1 Gene: May be involved in zinc transport out of the cell. ZNT1_HUMAN,Q9Y6M5

(2) Zinc transporter 2 (1p36.11) , ZNT2, SLC30A2, TNZD, PP12488.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A2&keywords=ZNT2

(Sinkin erittyminen äidinmaitoon. Sinkinpuute tyyppi).

The protein encoded by this gene is a zinc transporter that acts as a homodimer. The encoded protein plays a role in secreting zinc into breast milk. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

SLC30A2 (Solute Carrier Family 30 Member 2) is a Protein Coding gene. Diseases associated with SLC30A2 include Zinc Deficiency, Transient Neonatal and Acrodermatitis Enteropathica, Zinc-Deficiency Type. Among its related pathways are Metal ion SLC transporters and Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity. An important paralog of this gene is SLC30A3.

(3) ZNT3, SCL30A3 ( 2p23.3)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A3&keywords=ZNT3

GeneCards Summary for SLC30A3 Gene

SLC30A3 (Solute Carrier Family 30 Member 3) is a Protein Coding gene. Diseases associated with SLC30A3 include Hyperekplexia. Among its related pathways are Metal ion SLC transporters and Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc-transporting ATPase activity. An important paralog of this gene is SLC30A2. UniProtKB/Swiss-Prot Summary for SLC30A3 Gene Involved in accumulation of zinc in synaptic vesicles. ZNT3_HUMAN,Q99726

(4) ZNT4 , SLC30A4(15q21.1)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A4&keywords=ZNT4 Zinc is the second most abundant trace metal in the human body. It is an essential element, serving both a structural role, as in the formation of zinc fingers in DNA-binding proteins, and a catalytic role in metalloenzymes, such as pancreatic carboxypeptidases (e.g., MIM 114852), alkaline phosphatases (e.g., MIM 171760), various dehydrogenases, and superoxide dismutases (e.g., MIM 147450). SLC30A4, or ZNT4, belongs to the ZNT family of zinc transporters. ZNTs are involved in transporting zinc out of the cytoplasm and have similar structures, consisting of 6 transmembrane domains and a histidine-rich cytoplasmic loop (Huang and Gitschier, 1997 [PubMed 9354792]).[supplied by OMIM, Mar 2008] GeneCards Summary for SLC30A4 Gene SLC30A4 (Solute Carrier Family 30 Member 4) is a Protein Coding gene. Diseases associated with SLC30A4 include Acrodermatitis Enteropathica, Zinc-Deficiency Type and Acrodermatitis. Among its related pathways are Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A2. Probably involved in zinc transport out of the cytoplasm, maybe by sequestration into an intracellular compartment. ZNT4_HUMAN,O14863

(5) ZNT5 (SLC30A5) (5q13.1-q13.29 , ZNTL1, HZTL1

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A5&keywords=ZNT5 Entrez Gene Summary for SLC30A5 Gene This gene encodes a member of the SLC30A/ZnT family of zinc transporter proteins. ZnT proteins mediate both cellular zinc efflux and zinc sequestration into membrane-bound organelles. The encoded protein plays a role in the early secretory pathway as a heterodimer with zinc transporter 6, and may also regulate zinc sequestration into secretory granules of pancreatic beta cells. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Oct 2011] GeneCards Summary for SLC30A5 Gene SLC30A5 (Solute Carrier Family 30 Member 5) is a Protein Coding gene. Diseases associated with SLC30A5 include Acrodermatitis Enteropathica, Zinc-Deficiency Type and Nonsyndromic Deafness. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A7. UniProtKB/Swiss-Prot Summary for SLC30A5 Gene Functions as a zinc transporter. May be a transporter of zinc into beta cells in order to form insulin crystals. Partly regulates cellular zinc homeostasis. Required with ZNT7 for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs). Transports zinc into the lumens of the Golgi apparatus and vesicular compartments where ALPs locate, thus, converting apoALPs to holoALPs. Required with ZNT6 and ZNT7 for the activation of TNAP. ZNT5_HUMAN,Q8TAD4

(6) ZNT6, SLC30A6, (2p22.3), MST103, MSTP103.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A6&keywords=ZNT6 Entrez Gene Summary for SLC30A6 Gene This gene encodes a member of a family of proteins that function as zinc transporters. This protein can regulate subcellular levels of zinc in the Golgi and vesicles. Expression of this gene is altered in the Alzheimer's disease brain plaques. [provided by RefSeq, Aug 2016] GeneCards Summary for SLC30A6 Gene SLC30A6 (Solute Carrier Family 30 Member 6) is a Protein Coding gene. Diseases associated with SLC30A6 include Alzheimer Disease and Myasthenic Syndrome, Congenital, 5. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A5. UniProtKB/Swiss-Prot Summary for SLC30A6 Gene Zinc-efflux transporter which allocates the cytoplasmic zinc to the trans-Golgi network (TGN) as well as the vesicular compartment. ZNT6_HUMAN,Q6NXT4

(7) ZNT7, SLC30A7 . Zinc transporter like 2, ZNTL2.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A7&keywords=ZNT7Entrez Gene Summary for SLC30A7 Gene. Zinc functions as a cofactor for numerous enzymes, nuclear factors, and hormones and as an intra- and intercellular signal ion. Members of the zinc transporter (ZNT)/SLC30 subfamily of the cation diffusion facilitator family, such as SLC30A7, permit cellular efflux of zinc (Seve et al., 2004 [PubMed 15154973]).[supplied by OMIM, Mar 2008] GeneCards Summary for SLC30A7 Gene

SLC30A7 (Solute Carrier Family 30 Member 7) is a Protein Coding gene. Diseases associated with SLC30A7 include Joubert Syndrome 1 and Acrodermatitis Enteropathica, Zinc-Deficiency Type. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity. An important paralog of this gene is SLC30A5. UniProtKB/Swiss-Prot Summary for SLC30A7 Gene Seems to facilitate zinc transport from the cytoplasm into the Golgi apparatus. Partly regulates cellular zinc homeostasis. Required with ZNT5 for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs). Transports zinc into the lumens of the Golgi apparatus and the vesicular compartments where ALPs locate, thus, converting apoALPs to holoALPs. Required with ZNT5 and ZNT6 for the activation of TNAP (By similarity). ZNT7_HUMAN,Q8NEW0
 

(8), ZNT8, SLC30A8, (8q24.11)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A8&keywords=ZNT8 Entrez Gene Summary for SLC30A8 Gene. The protein encoded by this gene is a zinc efflux transporter involved in the accumulation of zinc in intracellular vesicles. This gene is expressed at a high level only in the pancreas, particularly in islets of Langerhans. The encoded protein colocalizes with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Allelic variants of this gene exist that confer susceptibility to diabetes mellitus, noninsulin-dependent (NIDDM). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]. GeneCards Summary for SLC30A8 Gene. SLC30A8 (Solute Carrier Family 30 Member 8) is a Protein Coding gene. Diseases associated with SLC30A8 include Diabetes Mellitus, Noninsulin-Dependent and Diabetes Mellitus. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A2. UniProtKB/Swiss-Prot Summary for SLC30A8 Gene. Facilitates the accumulation of zinc from the cytoplasm into intracellular vesicles, being a zinc-efflux transporter. May be a major component for providing zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic beta-cells. ZNT8_HUMAN,Q8IWU4

(9) ZNT9, SLC30A9.(4p13), GRIP1- dependent Nuclear Receptor Coactivator, GAC63, Chromosome4 OREF1, BILAPES, HuEL.
 GeneCards Summary for SLC30A9 Gene

SLC30A9 (Solute Carrier Family 30 Member 9) is a Protein Coding gene. Diseases associated with SLC30A9 include Birk-Landau-Perez Syndrome and Hemochromatosis, Type 5. Among its related pathways are Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and nuclear receptor transcription coactivator activity. UniProtKB/Swiss-Prot Summary for SLC30A9 Gene Acts as a zinc transporter involved in intracellular zinc homeostasis (PubMed:28334855). Functions as a secondary coactivator for nuclear receptors by cooperating with p160 coactivators subtypes. Plays a role in transcriptional activation of Wnt-responsive genes (By similarity). ZNT9_HUMAN,Q6PML9 Quaternary structure: Interacts with GRIP1, ESR1 and AR.

(10) ZNT10, SLC30A10, (1q41), Manganese Transporter SLC30 A19, HMNDYT1, HMDPC, ZRC1, ZNT8.
Entrez Gene Summary for SLC30A10 Gene This gene is highly expressed in the liver and is inducible by manganese. Its protein product appears to be critical in maintaining manganese levels, and has higher specificity for manganese than zinc. Loss of function mutations appear to result in a pleomorphic phenotype, including dystonia and adult-onset parkinsonism. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]GeneCards Summary for SLC30A10 Gene SLC30A10 (Solute Carrier Family 30 Member 10) is a Protein Coding gene. Diseases associated with SLC30A10 include Hypermanganesemia With Dystonia 1 and Hypermanganesemia With Dystonia. Among its related pathways are Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity. An important paralog of this gene is SLC30A1. UniProtKB/Swiss-Prot Summary for SLC30A10 Gene. Plays a pivotal role in manganese transport. Manganese is an essential cation for the function of several enzymes, including some crucially important for the metabolism of neurotransmitters and other neuronal metabolic pathways. However, elevated levels of manganese are cytotoxic and induce oxidative stress, mitochondrial dysfunction and apoptosis. Acts as manganese efflux transporter and confers protection against manganese-induced cell death (PubMed:22341972, PubMed:22341971, PubMed:25319704, PubMed:27226609, PubMed:27307044). Also acts as zinc transporter involved in zinc homeostasis. Seems to mediate zinc transport into early endosomes and recycling endosomes to prevent zinc toxicity; the function may be regulated by heterodimerization with other zinc transporters of the SLC30A subfamily. The SLC30A3:SLC30A10 heterodimer is involved in zinc transport-dependent regulation of the EGFR/ERK transduction pathway in endosomes. May be involved in regulation of zinc-dependent senescence of vascular smooth muscle cells (PubMed:22706290, PubMed:22427991, PubMed:26728129). ZNT10_HUMAN,Q6XR72 Protein attributes for SLC30A10 Gene Size: 485 amino acids , Molecular mass: 52684 Da . Quaternary structure: Forms homodimers. Forms heterodimers and high-molecular weight oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is mediated by covalent-bound tyrosine residues and occurs probably in a tissue-specific manner. Miscellaneous: [Isoform 2]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. SequenceCaution: Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; Evidence={ECO:0000305};

(11) ZNT tästä eteenpäin ei löydy geenejä tällä perhenimellä  SLC30A.
9.6. 2020 ZNT perheen geeneistä Gene Cards lähteestä. hakusanana  ZNT , numerot 1-10 tai  SCL30A numerot 1-10.
Klo 12:02.

HYPERGLYCEMIA , ACE2, haku, 44 vastausta., 10 ensimmäistä.

44 results

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1

Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic.

Brufsky A. J Med Virol. 2020 Apr 15. doi: 10.1002/jmv.25887. Online ahead of print. PMID: 32293710 Review.

Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS. 

2.

ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.

Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY. Diabetes. 2016 Jan;65(1):85-95. doi: 10.2337/db15-0399. Epub 2015 Jul 29. PMID: 26224885 Free PMC article.

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 

3. 

Activation of ACE2/angiotensin (1-7) attenuates pancreatic β cell dedifferentiation in a high-fat-diet mouse model.

Xuan X, Gao F, Ma X, Huang C, Wang Y, Deng H, Wang S, Li W, Yuan L. Metabolism. 2018 Apr;81:83-96. doi: 10.1016/j.metabol.2017.12.003. Epub 2017 Dec 7. PMID: 29225087

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing β cell dedifferentiation during …

4

ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice.

Shoemaker R, Yiannikouris F, Thatcher S, Cassis L. Am J Physiol Endocrinol Metab. 2015 Oct 1;309(7):E621-31. doi: 10.1152/ajpendo.00054.2015. Epub 2015 Aug 4. PMID: 26389599 Free PMC article.

Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset of type 2 diabetes (T2D). Pancreatic islets express RAS components, including angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)]. Overexpression of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The purpose of this study was to determine if deficiency of endogenous ACE2 contributes to islet dysfunction and T2D. We hypothesized that ACE2 deficiency potentiates the decline in β-cell function and augments the development of diet-induced T2D. Male Ace2(+/y) or Ace2(-/y) mice were fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1-7). At 4 mo, while both genotypes of HF-fed mice developed a similar level of insulin resistance, adaptive hyperinsulinemia was reduced in Ace2(-/y) vs. Ace2(+/y) mice. Similarly, in vivo glucose-stimulated insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2(-/y) compared with Ace2(+/y) mice, resulting in augmented hyperglycemia. The average islet area was significantly smaller in both LF- and HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Additionally, β-cell mass and proliferation were reduced significantly in HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Neither infusion of Los nor Ang-(1-7) was able to correct impaired in vivo GSIS of HF-fed ACE2-deficient mice. These results demonstrate a critical role for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to HF feeding through regulation of β-cell proliferation and growth. 

5.

Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice.

Zhao S, Ghosh A, Lo CS, Chenier I, Scholey JW, Filep JG, Ingelfinger JR, Zhang SL, Chan JSD. Endocrinology. 2018 Feb 1;159(2):836-852. doi: 10.1210/en.2017-00752. PMID: 29211853 Free PMC article.

We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 in Akita mice attenuated hypertension, renal injury, tubulointerstitial fibrosis, and the urinary albumin/creatinine ratio. Furthermore, loss of Nrf2 upregulated RPTC Ace2 and MasR expression, increased urinary Ang 1-7 levels, and downregulated expression of Agt, ACE, and profibrotic genes in Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose stimulation of Nrf2 nuclear translocation, Agt, and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes.

Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes.

Cherney DZ, Xiao F, Zimpelmann J, Har RL, Lai V, Scholey JW, Reich HN, Burns KD. Can J Physiol Pharmacol. 2014 Aug;92(8):703-6. doi: 10.1139/cjpp-2014-0065. Epub 2014 May 15. PMID: 24920267

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be renoprotective. We determined whether urinary ACE2 enzyme activity and protein levels (ELISA), as well as angiotensinogen and ACE, are elevated during clamped euglycemia (4-6 mmol·L(-1)) in patients with uncomplicated type 1 diabetes (T1D, n = 58) compared with normoglycemic controls (n = 21). We also measured the effect of clamped hyperglycemia (9-11 mmol·L(-1)) on each urinary factor in T1D patients. Urinary ACE2 activity and protein levels were higher during clamped euglycemia in T1D compared with the controls (p < 0.0001). In contrast, urinary angiotensinogen (AGT) levels (p = 0.27) and ACE excretion (p = 0.68) did not differ. In response to clamped hyperglycemia in T1D, urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2 activity as well as angiotensinogen and ACE levels remained unchanged. Urinary ACE2 activity and protein expression are increased in T1D patients prior to the onset of clinical complications. Further work is required to determine the functional role of urinary ACE2 in early T1D.

Keywords: ECA2 urinaire; diabetes mellitus; diabète sucré; urinary ACE2. 
7.

Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.

Salem ES, Grobe N, Elased KM. Am J Physiol Renal Physiol. 2014 Mar 15;306(6):F629-39. doi: 10.1152/ajprenal.00516.2013. Epub 2014 Jan 22. PMID: 24452639 Free PMC article.

Abstract

Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status.
8. 

High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria.

Park SE, Kim WJ, Park SW, Park JW, Lee N, Park CY, Youn BS. Eur J Endocrinol. 2013 Jan 17;168(2):203-10. doi: 10.1530/EJE-12-0782. Print 2013 Feb. PMID: 23144053

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) plays an important role in glucose metabolism and renal function. However, the relationship between ACE2 and hyperglycemia or microalbuminuria has not been established in humans. We investigated whether urinar …

9.

Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice.

Somineni HK, Boivin GP, Elased KM. J Endocrinol. 2014 Apr 22;221(2):235-51. doi: 10.1530/JOE-13-0532. Print 2014 May. PMID: 24756098 Free PMC article.Angiotensin II (Ang II) is involved in induction and progression of renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A disintegrin and metalloproteinase 17 (ADAM17)-mediated shedding of renal ACE2 contribute to diabetic nephropathy pathogenesis. Lifestyle modification and metformin are recommended as initial therapies for most patients with type 2 diabetes. The aim of this study was to investigate whether exercise training and/or metformin improve glucose homeostasis and albuminuria and downregulate renal ADAM17 and ACE2 shedding in db/db mice. Seven-week-old normal and db/db mice were subjected either to a sedentary existence or exercise training with and without metformin (150 mg/kg per day) for 10 weeks. Exercise training significantly lowered blood glucose, urinary albumin and ACE2 excretion in db/db mice. ADAM17 and ACE2 proteins were co-localized in cortical tubules of the kidney, indicating a possible interaction. Metformin treatment was effective in lowering hyperglycemia only during the first 2 weeks of treatment. Increased renal ADAM17 in 17-week-old db/db mice was corrected by physical exercise but not metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. In conclusion, exercise training alone and in combination with metformin prevented shedding of renal ACE2 by decreasing ADAM17 protein. Urinary ACE2 could serve as a prognostic tool for the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection.

10

Angiotensin II type 2 receptor and angiotensin-converting enzyme 2 mediate ischemic renal injury in diabetic and non-diabetic rats.

Sharma N, Malek V, Mulay SR, Gaikwad AB. Life Sci. 2019 Oct 15;235:116796. doi: 10.1016/j.lfs.2019.116796. Epub 2019 Aug 27. PMID: 31470003

However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. ...Co-a … Conclusion: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.
Keywords: ACE2 activator; AT2R agonist; Diabetes; Ischemic renal injury; Renin-angiotensin system.

ACE2 funktioineen tutkijoiden fokuksessa

https://pubmed.ncbi.nlm.nih.gov/32413319/

Metaboliset taudit pandemian aikana

. 2020 May 12;14(4):597-600.

doi: 10.1016/j.dsx.2020.05.025. Online ahead of print.

Mechanism of Inflammatory Response in Associated Comorbidities in COVID-19

Thays Maria Costa de Lucena  ¹ , Ariane Fernandes da Silva Santos  ¹ , Brenda Regina de Lima  ¹ , Maria Eduarda de Albuquerque Borborema  ¹ , Jaqueline de Azevêdo Silva  ²

Affiliations

• PMID: 32417709
• PMCID: PMC7215143
• DOI: 10.1016/j.dsx.2020.05.025

Free PMC article

Abstract

Background and aims: The outbreak of the new coronavirus, SARS-CoV-2, causes a respiratory disease and individuals with pre-existing cardiometabolic disorders display worse prognosis through the infection course. The aim of this minireview is to present epidemiological data related to metabolic comorbidities in association with the SARS-CoV-2.
Methods: This is a narrative mini-review with Pubmed search until April 23, 2020 using the keywords COVID-19, SARS-CoV-2, treatment of coronavirus and following terms: diabetes mellitus, obesity, arterial hypertension, ACE-inhibitors, cytokine storm, immune response and vitamin D.
Results: Studies indicate that obese individuals are more likely to develop infections, and that adipose tissue serves as a pathogen reservoir. In diabetic individuals higher rate of inflammatory processes is seen due to constant glucose recognition by C type lectin receptors. Hypertensive individuals, usually grouped with other conditions, are treated with drugs to reduce blood pressure mostly through ACEi and ARB, that leads to increased ACE2 expression, used by SARS-CoV-2 for human's cell entry. Until now, the studies have shown that individuals with those conditions and affected by COVID-19 present an uncontrolled release of pro-inflammatory cytokines and an unbalanced immune response, leading to the cytokine storm phenomenon. Vitamin D is highlighted as a potential therapeutic target, because in addition to acting on the immune system, it plays an important role in the control of cardiometabolic diseases.
Conclusion: Currently, since there is no proven and effective antiviral therapy for SARS-CoV-2, the efforts should focus on controlling inflammatory response and reduce the risks of associated complications.

Keywords: Diabetes mellitus; Hypertension arterial; Immune response; Obesity; Vitamin D.

Copyright © 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

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COP1, RFWD2 E3 ubikitiiniligaasi ja insuliinin eritys

https://www.ncbi.nlm.nih.gov/pubmed/26627735

Cell. 2015 Dec 3;163(6):1457-67. doi: 10.1016/j.cell.2015.10.076. Epub 2015 Nov 25.

β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1.

Suriben R¹, Kaihara KA², Paolino M¹, Reichelt M³, Kummerfeld SK⁴, Modrusan Z⁵, Dugger DL¹, Newton K¹, Sagolla M³, Webster JD³, Liu J⁴, Hebrok M², Dixit VM⁶.

Author information

Abstract

A variety of signals finely tune insulin secretion by pancreatic β cells to prevent both hyper-and hypoglycemic states. Here, we show that post-translational regulation of the transcription factors ETV1, ETV4, and ETV5 by the ubiquitin ligase COP1 (also called RFWD2) in β cells is critical for insulin secretion. Mice lacking COP1 in β cells developed diabetes due to insulin granule docking defects that were fully rescued by genetic deletion of Etv1, Etv4, and Etv5. Genes regulated by ETV1, ETV4, or ETV5 in the absence of mouse COP1 were enriched in human diabetes-associated genes, suggesting that they also influence human β-cell pathophysiology. In normal β cells, ETV4 was stabilized upon membrane depolarization and limited insulin secretion under hyperglycemic conditions. Collectively, our data reveal that ETVs negatively regulate insulin secretion for the maintenance of normoglycemia.

Copyright © 2015 Elsevier Inc. All rights reserved.

Comment in

• Metabolism: Keeping insulin secretion in check. [Nat Rev Mol Cell Biol. 2016]

PMID:

26627735

DOI:

10.1016/j.cell.2015.10.076

[Indexed for MEDLINE]

Free full text

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2'O-ribose methylation

https://www.sciencedirect.com/science/article/pii/S1874939918300804

Highlights

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Ribose 2’-O-methylation is very common RNA modification omnipresent in cellular RNAs (rRNAs/tRNAs/mRNAs/sn(sno)RNAs/miRNAs…).

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Formation of 2’-O-methylated residues is insured by both protein stand-alone enzymes and by C/D-box sno(s)RNP complexes.

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Ribose methylation in RNA is dynamic and responds to physiological state of the cell.

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Ribose methylation is important for regulation of RNA stability, mRNA splicing and translation, as well as innate immune response.

Description

https://www.ebi.ac.uk/interpro/entry/InterPro/IPR013123/

Most cellular RNAs undergo a number of post-transcriptional nucleoside modifications. While the biological role of many of these modifications is unknown, some have been shown to be necessary for cell growth or for resistance to antibiotics

^{[1, 2]}

. One of the most common modifications is 2'O-ribose methylation catalysed by the RNA 2'O-ribose methyltransferases, a large enzyme family that transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the 2'-OH group of the backbone ribose

^[3]

.

This entry represents a substrate-binding domain found in a variety of bacterial and mitochondrial RNA 2'-O ribose methyltransferases. These include the bacterial enzyme RlmB, which specifically methylates the conserved nucleotide guanosine 2251 in 23S RNA, and PET56, which specifically methylates the equivalent guanosine in mitochondrial 21S RNA

^{[4, 1]}

. This domain forms a four-stranded mixed beta sheet similar to that found in other RNA binding enzymes

^[5]

. It shows considerable conformational flexibility which is thought to be important for its ability to bind RNA.

Wikipedia

2'-O-methylation

From Wikipedia, the free encyclopedia

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2'-O-methyl-adenosine, a modified adenosine.

2'-O-methylation is a common nucleoside modification of RNA, where a methyl group is added to the 2' hydroxyl of the ribose moiety of a nucleoside, producing a methoxy group. 2'-O-methylated nucleosides are mostly found in ribosomal RNA and small nuclear RNA and occur in the functionally essential regions of the ribosome and spliceosome.^[1] Currently, about 1210 2'-O-methylations (2'-O-Me) have been identified in mammals and yeast and deposited in RMBase (RNA Modification Base) database.^[2]
Having the chemical properties intermediate between RNA and DNA, 2'-O-methylation is presumed to have one of the reactive group of RNA molecules on early earth that would have given rise to DNA.^[3]
Recently a novel method to map 2'-O ribose methylations by high throughput sequencing has been published.^[4] The method is quantitative and maps all modifications in a single experiment.

RIBOOSI , cADPr

cADPr, syklinen ADPriboosi

• Review
• Published: 31 January 2000

Cyclic ADP-ribose

• Andreas H. Guse 

Journal of Molecular Medicine volume 78, pages26–35(2000) Cite this article

Abstract.

The Ca²⁺-mobilizing natural compound cyclic ADP-ribose was discovered in sea urchin egg homogenates. Recently the involvement of cyclic ADP-ribose in Ca²⁺ signaling has been demonstrated in diverse biological systems spanning protozoa, plants, and cells from invertebrate, mammalian, and human sources. ADP-ribosyl cyclases synthesize cyclic ADP-ribose. Several candidate proteins for these enzymes have been proposed, including membrane-bound NAD⁺ glycohydrolases such as CD38 and soluble enzyme activities from various tissues and cells. Ca²⁺ mobilization by cyclic ADP-ribose is believed to proceed via the ryanodine receptor/Ca²⁺ channel, probably via binding proteins for cyclic ADP-ribose. Several antagonistic derivatives of cyclic ADP-ribose have been synthesized, some of which have been successfully used to demonstrate the involvement of cyclic ADP-ribose in sea urchin egg fertilization, glucose-dependent insulin secretion in pancreatic β-cells, and activation and proliferation of human T-lymphocytes.

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