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Kidney International Jan 1986This very brief summary of the various possible contributions of PG to normal and abnormal renal function should highlight the problem of assigning a specific role to PG... (Review)
Review
This very brief summary of the various possible contributions of PG to normal and abnormal renal function should highlight the problem of assigning a specific role to PG in overall renal physiology and pathophysiology. PG produced in specific segments of the nephron will affect specific functions occurring in this segment. These effects need not necessarily be reflected in the overall renal function. Also in some cases, the determinant may not be prostaglandins, that is, cyclooxygenase derivatives of AA, but perhaps lipoxygenase or epoxygenase products that influence the functional parameters of the specific segment. Despite the multitude of renal functions that may be influenced by PG, we would like to propose a teleological hypothesis for an overall role of PG in the kidney, that is, that of cytoprotective agents. Renal vasodilatatory prostaglandins will maintain renal blood flow when the latter is challenged, thus, preventing hypoxic injury to the tissue. Endogenous prostaglandins may also protect tubular cells from extreme environmental changes as may occur on both the luminal and contraluminal sides. For example, tubular cells may be exposed to luminal fluid that may vary from hypotonic to hypertonic, from alkaline to acid, and so forth. Similarly, the interstitial fluid osmolality and solute composition is subject to considerable variations which may be opposite to those existing on the urinary side. The role of PG might be to maintain the internal milieu of the cells exposed to such extreme changes in environment. This could be accomplished by changing the permeability characteristics of the membranes and the function of pumps. Thus, specific PGs could dampen the hormonal response to protect the specific nephron segment, which might otherwise suffer injury. This hypothesis might also help to explain why the effect of PG administration or inhibition of PG synthesis may vary considerably depending on the overall physiological state of the subject: Maintenance of a local internal milieu may require different responses from those required for total body homeostasis.
Topics: Animals; Arachidonic Acid; Arachidonic Acids; Glomerular Filtration Rate; Kidney; Kidney Diseases; Lipoxygenase; Mixed Function Oxygenases; Nephrons; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rabbits; Rats; Renal Circulation; Renin
PubMed: 3083150
DOI: 10.1038/ki.1986.13 -
Current Opinion in Nephrology and... May 2013This review will examine advances in our understanding of the association between high-density lipoprotein (HDL) function and cardiovascular disease (CVD) in patients... (Review)
Review
PURPOSE OF REVIEW
This review will examine advances in our understanding of the association between high-density lipoprotein (HDL) function and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD).
RECENT FINDINGS
Large randomized statin trials and related meta-analyses confirm that lipid-lowering therapy benefits patients with mild to moderate CKD, leaving a degree of residual cardiovascular risk similar to that documented in the general population. However, patients with advanced CKD on dialysis show little to no cardiovascular benefits from lipid-lowering therapy and have an exaggerated residual cardiovascular risk. HDL quantity and functionality may explain some of the residual risk. CKD modulates the level, composition and functionality of HDL, including impaired cholesterol acceptor function and pro-inflammatory effects. Although these abnormalities prevail in CKD, they do not track together and thus support the idea of separate and distinct mechanistic pathways for each of these critical functions of HDL.
SUMMARY
CKD-induced perturbations in HDL composition, metabolism and functionality may contribute to the excess CVD in patients with CKD and present new therapeutic targets for intervention in this population.
Topics: Biomarkers; Cardiovascular Diseases; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Lipoproteins, HDL; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 23470818
DOI: 10.1097/MNH.0b013e32835fe47f -
American Journal of Physiology.... May 2000The C-peptide of proinsulin is important for the biosynthesis of insulin but has for a long time been considered to be biologically inert. Data now indicate that... (Review)
Review
The C-peptide of proinsulin is important for the biosynthesis of insulin but has for a long time been considered to be biologically inert. Data now indicate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to a G protein-coupled surface receptor, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways. The association rate constant, K(ass), for C-peptide binding to endothelial cells, renal tubular cells, and fibroblasts is approximately 3. 10(9) M(-1). The binding is stereospecific, and no cross-reaction is seen with insulin, proinsulin, insulin growth factors I and II, or neuropeptide Y. C-peptide stimulates Na(+)-K(+)-ATPase and endothelial nitric oxide synthase activities. Data also indicate that C-peptide administration is accompanied by augmented blood flow in skeletal muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin excretion, and improved nerve function, all in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects. The possibility exists that C-peptide replacement, together with insulin administration, may prevent the development or retard the progression of long-term complications in type 1 diabetes.
Topics: Amino Acid Sequence; Animals; Blood Glucose; C-Peptide; Humans; Kidney; Molecular Sequence Data; Nervous System Physiological Phenomena; Physiology; Sequence Homology; Signal Transduction
PubMed: 10780930
DOI: 10.1152/ajpendo.2000.278.5.E759 -
Methods in Molecular Biology (Clifton,... 2022Despite an enormous investment of clinical and financial resources, chronic kidney disease (CKD) remains a global health threat. The lack of reliable in vitro systems...
Despite an enormous investment of clinical and financial resources, chronic kidney disease (CKD) remains a global health threat. The lack of reliable in vitro systems that can efficiently mimic the renal and glomerular environment has hampered our ability to successfully develop novel and more renal specific drugs. Even though some success in generating in vitro tubule analogues and kidney organoids has been described, a major challenge remains for the in vitro assembly of the filtration unit of the kidney, the glomerulus. We have recently developed a novel glomerulus-on-a-chip system that mimics the characteristic and functionality of the glomerular filtration barrier, including its response to injury. This system recapitulates the functions and structure of the in vivo glomerulus, including permselectivity; indeed, we have confirmed free diffusion of insulin as well as impermeability to physiological concentrations of albumin. Exposure to nephrotoxic agents like puromycin aminonucleoside leads to a significant increase in albumin leakage. When exposed to sera from patients with anti-podocyte autoantibodies, the chip shows albumin leakage to an extent proportional to in vivo clinical data, phenomenon not observed with sera from either healthy controls, confirming functional response to injury. We describe here the detailed procedure to obtain a glomerulus-on-a-chip system that replicates both phenotypically and functionally the in vivo glomerular microenvironment.
Topics: Albumins; Glomerular Filtration Barrier; Humans; Kidney Diseases; Kidney Glomerulus; Lab-On-A-Chip Devices; Podocytes
PubMed: 34520010
DOI: 10.1007/978-1-0716-1693-2_8 -
Nephrology, Dialysis, Transplantation :... Jun 2022Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of veverimer on serum bicarbonate and physical function in diabetic patients with chronic kidney disease and metabolic acidosis: subgroup analysis from a randomized, controlled trial.
BACKGROUND
Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes.
METHODS
This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo.
RESULTS
At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001).
CONCLUSIONS
Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.
Topics: Acidosis; Bicarbonates; Diabetes Mellitus; Humans; Polymers; Quality of Life; Renal Insufficiency, Chronic; Sodium Bicarbonate
PubMed: 34240198
DOI: 10.1093/ndt/gfab209 -
Transplant International : Official... Apr 2008The effect of both donor renal mass and gender on renal function, in both gender recipients, was examined. Qualifying consecutive living-donor renal transplants (n =...
The effect of both donor renal mass and gender on renal function, in both gender recipients, was examined. Qualifying consecutive living-donor renal transplants (n = 730) were stratified into 4 donor-recipient groups: female-female (n = 177), male-female (n = 151), female-male (n = 240), male-male (n = 162). Groups were equivalent in age, race, body mass index (BMI), match, ischemia time, operative time, and estimated glomerular filtration rate (eGFR). Female recipients had lower serum creatinine (Cr(s)). Male recipients had higher Cr(s) wherever they received a female allograft. Male recipients of male kidneys had a higher eGFR than all other groups for 3 years. Renal function of the recipient correlated with the renal mass of the donor within each group. Male and female kidneys functioned equivalently in the female-recipient environment. Large nephron-mass male donor kidneys function more poorly in female recipients. The male kidney loses 15-20 ml/min eGFR in the female host. The diminished graft function may be related to androgen deprivation. Female and male donor kidneys function equivalently in the male recipient if adjusted for renal mass transplanted. Female kidneys improve eGFR by 7-10 ml/min by being transplanted into a male environment. Donor renal mass and gender affect recipient graft function Expectations of ultimate recipient renal function should take into account both the gender and mass disparity of the donor-recipient pair.
Topics: Adult; Body Mass Index; Female; Glomerular Filtration Rate; Graft Survival; Humans; Kidney; Kidney Transplantation; Living Donors; Male; Middle Aged; Sex Factors
PubMed: 18086285
DOI: 10.1111/j.1432-2277.2007.00617.x -
American Journal of Physiology. Renal... Apr 2019
Topics: Cardiovascular Physiological Phenomena; Female; Humans; Kidney; Leadership; Male; Metabolism; Physiology; Sex Characteristics; Societies, Scientific; United States
PubMed: 30759024
DOI: 10.1152/ajprenal.00019.2019 -
Physiological Reviews Oct 2000Renal proximal tubular reabsorption of P(i) is a key element in overall P(i) homeostasis, and it involves a secondary active P(i) transport mechanism. Among the... (Review)
Review
Renal proximal tubular reabsorption of P(i) is a key element in overall P(i) homeostasis, and it involves a secondary active P(i) transport mechanism. Among the molecularly identified sodium-phosphate (Na/P(i)) cotransport systems a brush-border membrane type IIa Na-P(i) cotransporter is the key player in proximal tubular P(i) reabsorption. Physiological and pathophysiological alterations in renal P(i) reabsorption are related to altered brush-border membrane expression/content of the type IIa Na-P(i) cotransporter. Complex membrane retrieval/insertion mechanisms are involved in modulating transporter content in the brush-border membrane. In a tissue culture model (OK cells) expressing intrinsically the type IIa Na-P(i) cotransporter, the cellular cascades involved in "physiological/pathophysiological" control of P(i) reabsorption have been explored. As this cell model offers a "proximal tubular" environment, it is useful for characterization (in heterologous expression studies) of the cellular/molecular requirements for transport regulation. Finally, the oocyte expression system has permitted a thorough characterization of the transport characteristics and of structure/function relationships. Thus the cloning of the type IIa Na-P(i )cotransporter (in 1993) provided the tools to study renal brush-border membrane Na-P(i) cotransport function/regulation at the cellular/molecular level as well as at the organ level and led to an understanding of cellular mechanisms involved in control of proximal tubular P(i) handling and, thus, of overall P(i) homeostasis.
Topics: Absorption; Animals; Biological Transport, Active; Carrier Proteins; Electrophysiology; Gene Expression Regulation; Kidney Tubules, Proximal; Mice; Microvilli; Phosphates; Phylogeny; Protein Isoforms; Protein Structure, Secondary; Rabbits; Rats; Sequence Homology, Amino Acid; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type IIa; Symporters
PubMed: 11015617
DOI: 10.1152/physrev.2000.80.4.1373 -
American Journal of Physiology. Renal... Nov 2005This review article summarizes current knowledge about the locations and possible functions of annexin family members in the kidney. Beginning with an introduction on... (Review)
Review
This review article summarizes current knowledge about the locations and possible functions of annexin family members in the kidney. Beginning with an introduction on common structural and biochemical features as well as general functional characteristics of annexins, the paper focuses on individual members with documented and/or proposed physiological relevance for renal development, structure, and functions. Three main aspects of annexin function in kidney epithelia emerge from the available experimental data. First, annexins are required for membrane organization and membrane transport events required for the establishment/maintenance of epithelial polarity. Second, there is accumulating evidence of an association of annexins with ion channels, as membrane-guiding auxiliary proteins or modulators of channel activity. Last but not least, some annexins seem to work as extracellular autocrine modulators of receptor function under different physiological conditions.
Topics: Annexins; Binding Sites; Calcium; Cell Membrane; Humans; Ion Channels; Kidney; Membrane Potentials
PubMed: 16210453
DOI: 10.1152/ajprenal.00089.2005 -
International Journal of Molecular... Sep 2018In recent years, the TFCP2 (transcription factor cellular promoter 2)/TFCP2L1 (TFCP2-like 1)/UBP1 (upstream binding protein 1) subfamily of transcription factors has... (Review)
Review
In recent years, the TFCP2 (transcription factor cellular promoter 2)/TFCP2L1 (TFCP2-like 1)/UBP1 (upstream binding protein 1) subfamily of transcription factors has been attracting increasing attention in the scientific community. These factors are very important in cancer, Alzheimer's disease, and other human conditions, and they can be attractive targets for drug development. However, the interpretation of experimental results is complicated, as in principle, any of these factors could substitute for the lack of another. Thus, studying their hitherto little known functions should enhance our understanding of mechanisms of their functioning, and analogous mechanisms might govern their functioning in medically relevant contexts. For example, there are numerous parallels between placental development and cancer growth; therefore, investigating the roles of TFCP2, TFCP2L1, and UBP1 in the placenta may help us better understand their functioning in cancer, as is evidenced by the studies of various other proteins and pathways. Our review article aims to call the attention of the scientific community to these neglected functions, and encourage further research in this field. Here, we present a systematic review of current knowledge of the TFCP2/TFCP2L1/UBP1 subfamily in reproduction, embryonic development, renal function, blood-pressure regulation, brain function, and other processes, where their involvement has not been studied much until now.
Topics: Blood Pressure; Brain; DNA-Binding Proteins; Embryonic Development; Gene Expression Regulation; Humans; Kidney; Reproduction; Transcription Factors
PubMed: 30241344
DOI: 10.3390/ijms19102852