Evolutionary conservation of intrinsically unstructured regions in slit-diaphragm proteins

Vertebrate kidneys contribute to homeostasis by regulating electrolyte, acid-base balance, removing toxic metabolites from blood, and preventing protein loss into the urine. Glomerular podocytes constitute the blood-urine barrier, and podocyte slit-diaphragm (SD), a modified tight junction, contributes to the glomerular permselectivity. Nephrin, KIRREL1, podocin, CD2AP, and TRPC6 are crucial members of the SD that interact with each other and contribute to the SD’s structural and functional integrity. This study analyzed the distribution of these five essential SD proteins across the organisms for which the genome sequence is available. We found a diverse distribution of nephrin and KIRREL1 ranging from nematodes to higher vertebrates, whereas podocin, CD2AP, and TRPC6 are restricted to the vertebrates. Among invertebrates, nephrin and its orthologs consist of more immunoglobulin-3 domains, whereas in the vertebrates, CD80-like C2-set domains are predominant. In the case of KIRREL1 and its orthologs, more Ig domains were observed in invertebrates than vertebrates. Src Homology-3 (SH3) domain of CD2AP and SPFH domain of podocin are highly conserved among vertebrates. TRPC6 and its orthologs had conserved ankyrin repeats, TRP, and ion transport domains, except Chondrichthyes and Echinodermata, which do not possess the ankyrin repeats. Intrinsically unstructured regions (IURs) are conserved across the SD orthologs, suggesting IURs importance in the protein complexes that constitute the slit-diaphragm. For the first time, a study reports the evolutionary insights of vertebrate SD proteins and their invertebrate orthologs.

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Molecular Evolution of Podocyte Slit-diaphragm Proteins

10.1101/2020.11.03.366161 ◽

2020 ◽

Author(s):

NSK Mulukala ◽

V Kambhampati ◽

SAH Qadri ◽

AK Pasupulati

Keyword(s):

Protein Complexes ◽

Slit Diaphragm ◽

Ankyrin Repeats ◽

Protein Loss ◽

Acid Base Balance ◽

Src Homology 3 ◽

Base Balance ◽

Src Homology ◽

Spfh Domain ◽

First Time

AbstractVertebrates kidneys contribute to the homeostasis by regulating electrolyte, acid-base balance, and prevent protein loss into the urine. Glomerular podocytes constitute blood-urine barrier and podocyte slit-diaphragm, a modified tight junction contributes to the glomerular permselectivity. Nephrin, podocin, CD2AP, and TRPC6 are considered to be crucial members, which largely interact with each other and contribute to the structural and functional integrity of the slit-diaphragm. In this study, we analyzed the distribution of these four-key slit-diaphragm proteins across the organisms for which the genome sequence is available. We found that nephrin has a diverse distribution ranging from nematodes to higher vertebrates whereas podocin, CD2AP, and TRPC6 are predominantly restricted to the vertebrates. In the invertebrates nephrin and its orthologs consist of more immunoglobulin-3 and immunoglobulin-5 domains when compared to the vertebrates wherein, CD80-like C2-set Ig2 domains were predominant. Src Homology-3 (SH3) domain of CD2AP and SPFH domain of podocin are highly conserved among vertebrates. Although the majority of the TRPC6 and its orthologs had conserved ankyrin repeats, TRP, and ion transport domains, the orthologs of TRPC6 present in Rhincodon typus and Acanthaster planci do not possess the ankyrin repeats. Intrinsically unstructured regions (IURs), which are considered to contribute to the interactions among these proteins are largely conserved among orthologs of these proteins, suggesting the importance of IURs in the protein complexes that constitute slit-diaphragm. This study for the first time reports the evolutionary insights of vertebrate slit-diaphragm proteins and its invertebrate orthologs.

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P1803EFFICACY, SAFETY AND IMPACT ON RENAL FUNCTIONALITY OF ACETAZOLAMIDE TREATMENT IN PATIENTS WITH PMM2-CDG (AZATAX CLINICAL TRIAL)

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1803 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Mercedes Serano Guimaré ◽

Pedro Arango Sancho ◽

Víctor López Baez ◽

Elena Codina Sampera ◽

Yolanda Calzada Baños ◽

...

Keyword(s):

Clinical Trial ◽

Renal Ultrasound ◽

Second Phase ◽

Protein Loss ◽

Acid Base Balance ◽

Base Balance ◽

Renal Prognosis ◽

Intellectual Deficit ◽

Glycosylation Defect

Abstract Background and Aims Deficit of phosphomanomutase-(PMM2-CDG) is the most frequent congenital N-glycosylation defect, producing cerebellar syndrome with intellectual deficit and “stroke-like” episodes. It has been associated with renal alterations such as proteinuria, diffuse cortical hyperechogenicity and malformations. We evaluated efficacy, safety and renal repercussion of acetazolamide as a new therapeutic tool. Method First clinical trial in phase II including PMM2-CDG patients (5-21-years). First phase: 6 months treatment group with acetazolamide. Second phase: 5 weeks randomized withdrawal in responders (acetazolamide vs placebo), assessing renal functionality and effects of this medication. Dosing acetazolamide by 8 to 30mg/kg/day in 2-3 doses. Controls were performed at 3, 6, 14, 25 and 30 weeks determining acid-base balance, ionogram, renal function (creatinine) and Pr/Cr, Ca/Cr index and B2-microglobulin in first morning urine. All patients underwent in a bone densitometry study and renal ultrasound. Results 24 patients were included (mean age 12.3 ± 4.5 years). Bicarbonate levels and plasma pH were significantly lower at week 25(p <0.001). 13 patient needs to reduce acetazolamide dose due to excessive metabolic acidosis or asthenia. They showed a decrease in sodium (p=0.06), potassium (p<0.001) and serum calcium(p=0.030), although maintained in low normality limit with a decrease in protein loss(p=0.019) and increase in calcium/creatinine index(p=0.025) without B2-microglobulin alterations. The previously ultrasound renal described findings; the cortical hyperechogenicity was observed in 8.4% without renal dysfunction or associated nephrocalcinosis. One patient presented microlithiasis and another, symptomatic renal lithiasis. Densitometric study 69% of patients presented values in the range of osteopenia at the end of trial (-0.9 to -4.9SD, average of -2.36SD). Conclusion The efficacy of acetazolamide in the neurological symptoms of PMM2-CDG, due to an enzymatic stimulation mechanism mediated by acidosis, generates the possibility of chronic treatment with the drug in this group of patients, with possible renal adverse effects associated with long-term, overshadowing the skeletal and renal prognosis.

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THE INDICATORS OF BASAL METABOLISM IN INFLAMMATORY SYNDROME BACTERIAL ORIGIN: PREDICTORS OF PROGNOSIS OR THE NEED FOR TIMELY CORRECTION?

Russian Clinical Laboratory Diagnostics ◽

10.18821/0869-2084-2019-64-2-122-127 ◽

2019 ◽

Vol 64 (2) ◽

pp. 122-127

Author(s):

Yu. L. Ketsko ◽

A. V. Lunina ◽

O. A. Gusyakova ◽

E. V. Petrovskaya ◽

A. V. Lyamin ◽

...

Keyword(s):

Antibacterial Therapy ◽

Nutritional Therapy ◽

Basal Metabolism ◽

Protein Loss ◽

Acid Base Balance ◽

Logistic Analysis ◽

Therapy Strategy ◽

Base Balance ◽

Inflammatory Syndrome

The aim of the study was to determine the comparative significance of basal metabolism indicators and inflammatory process markers for the closest prognosis of patients in ICUs with systemic inflammation syndrome caused with infectious genesis. The paper presents the results of a retrospective analysis of the plan of treatment of 198 patients with confirmed clinical and laboratory signs of bacterial infection. The number of leukocytes, platelets, the percentage of lymphocytes, the concentration of procalcitonin, creatinine, bilirubin, C-reactive protein, acid-base balance values were determined in patients. Patients were assessed on a SOFA scale. The type of biomaterial for microbiological research was determined depending on the intended source of infectious inflammation. Identification of the isolated microorganisms was carried out using the MALDI ToF mass spectrometry method, followed by determination of antibiotic resistance. Empirical antibiotic therapy was prescribed upon admission of the patient to the ICU. Patients were switched to etiotropic antibacterial therapy after 48 hours, taking into account the results of a microbiological study. Determination of basal metabolic rate was carried out using the method of indirect calorimetry (CCM Express, Medical Graphics) with the calculation of basal metabolism, respiratory coefficient, absolute and relative amount of macronutrients. The calculation of the protein was made on the basis of the nitrogen level of the daily urine urea. Logistic analysis (ROC analysis) revealed that the antibacterial therapy strategy used, age, gender of patients, tinctorial properties of microorganisms isolated from patients, do not affect the nearest prognosis of the disease. On the contrary, SOFA score, the concentration of procalcitonin in the blood, and such parameters of the metabolic status as the need for kilocalories per kilogram of actual body weight and the percentage of protein calories significantly affect the nearest prognosis of the disease. The percentage of calories derived from protein metabolism, in the main exchange has a high reliable predictive value. The results of the study confirm the importance of adequate nutritional therapy in the treatment of patients with infectious inflammatory syndrome, including the calculation and correction of protein loss and total daily calorie.

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Higher Dietary Acidity is Associated with Lower Bone Mineral Density in Postmenopausal Iranian Women, Independent of Dietary Calcium Intake

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000207 ◽

2014 ◽

Vol 84 (3-4) ◽

pp. 0206-0217 ◽

Cited By ~ 8

Author(s):

Seyedeh-Elaheh Shariati-Bafghi ◽

Elaheh Nosrat-Mirshekarlou ◽

Mohsen Karamati ◽

Bahram Rashidkhani

Keyword(s):

Calcium Intake ◽

Dietary Calcium ◽

Dietary Calcium Intake ◽

Dietary Intakes ◽

Iranian Women ◽

Acid Base Balance ◽

Mineral Density ◽

Acid Base ◽

Base Balance ◽

Dietary Acid

Findings of studies on the link between dietary acid-base balance and bone mass are relatively mixed. We examined the association between dietary acid-base balance and bone mineral density (BMD) in a sample of Iranian women, hypothesizing that a higher dietary acidity would be inversely associated with BMD, even when dietary calcium intake is adequate. In this cross-sectional study, lumbar spine and femoral neck BMDs of 151 postmenopausal women aged 50 - 85 years were measured using dual-energy x-ray absorptiometry. Dietary intakes were assessed using a validated food frequency questionnaire. Renal net acid excretion (RNAE), an estimate of acid-base balance, was then calculated indirectly from the diet using the formulae of Remer (based on dietary intakes of protein, phosphorus, potassium, and magnesium; RNAERemer) and Frassetto (based on dietary intakes of protein and potassium; RNAEFrassetto), and was energy adjusted by the residual method. After adjusting for potential confounders, multivariable adjusted means of the lumbar spine BMD of women in the highest tertiles of RNAERemer and RNAEFrassetto were significantly lower than those in the lowest tertiles (for RNAERemer: mean difference -0.084 g/cm2; P=0.007 and for RNAEFrassetto: mean difference - 0.088 g/cm2; P=0.004). Similar results were observed in a subgroup analysis of subjects with dietary calcium intake of >800 mg/day. In conclusion, a higher RNAE (i. e. more dietary acidity), which is associated with greater intake of acid-generating foods and lower intake of alkali-generating foods, may be involved in deteriorating the bone health of postmenopausal Iranian women, even in the context of adequate dietary calcium intake.

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