Cell and Transport Physiology Extracellular Hypotonicity Increases NA, K-ATPase Cell Surface Expression Via Enhanced Na+ Influx in Cultured Renal Collecting Duct Cells Regulating Na+ Transport: Focus on Na+ Entry.
The aldosterone-sensitive distalnephron is the sight of final regulation of Na+ and K+ balance.Positive Na+ balance occurs in conditions (e.g., low renin hypertension,edema, etc.) that are very familiar to the clinician. More informationis needed about the processes that underlie positive Na+ balance.Long-term regulation is accomplished through changes in thesteady-state numbers of apical membrane channels and basolateralpumps. Short-term regulation of Na+ transport involves changesin their activity and/or rapid changes in their distributionbetween intracellular pools and the surface membrane. In thepaper by Feraille et al., the sequential steps of this adaptationare defined. The central determinant appears to be an increasein intracellular N+ entry, with subsequent increased extrusionby basolateral membrane Na+ pump activity. Although these changeswere initiated by hypotonic cell swelling, the change in Na+entry rather than any change in cell volume triggered the adaptiveresponse. Page 2537
Basic Mineral Metabolism Calcimimetic Compound Up-Regulates Decreased Calcium-Sensing Receptor Expression Level in Parathyroid Glands of Rats with Chronic Renal Insufficiency Calcimimetic Compound Up-Regulates Decreased Calcium-Sensing Receptor Expression Level In Parathyroid Glands Of Rats With Chronic Renal Insufficiency.
The mechanism by which calcimimeticdrugs decrease the secretion of PTH in uremia was explored ina rat model of chronic renal failure. Uremia is associated withproliferation of parathyroid cells and with decreased calciumreceptor (CaR) expression. The calcimimetic agent R-568 decreasedserum PTH levels and restored CaR mRNA expression levels tothat found in the sham operated control group. This drug wasalso associated with a decrease in parathyroid proliferatingcell nuclear antigen positive cells and with a decrease in parathyroidgland weight. These effects were independent of serum phosphorousand serum 1,25 dihydroxy vitamin D3 concentrations. Page 2579
Hemodynamics and Vascular Regulation Intravenous Delivery of PTH/PTHrP type I Receptor cDNA to Rats Decreases Heart Rate, Blood Pressure, Renal Tone, Renin Angiotensin System and Stress-Induced Cardiovascular Responses PTHrP (and PTH ?) - Cardiovascular Hormones.
PTH is a predictor of cardiovasculardeath in uremic patients. For different reasons mortality ishigher both at low and high PTH concentrations. Therefore informationon cardiovascular effects of PTH is of considerable interest,keeping cautiously in mind potential species differences. Theeffects of PTH, an endocrine hormone, and PTH related protein(PTHrP), a local autacoid, are mediated via the same PTHR1 receptor:The actions of PTHrP are imitated by PTH at high concentrationsnot seen physiologically, but potentially relevant in renalfailure. As reported elsewhere in this journal Fritsch et alelegantly overcame major methodological problems by systemicPTHR1 cDNA plasmid delivery. This strategy allowed them to furthercharacterize the effects of exogenous and endogenous PTHrP.They were able to document BP lowering, renal vasodilatation,inhibition of renin release and attenuation of stress responses.The importance of PTHrP as a cardiovascular agonist had to someextent been underestimated in the past. This interesting newreport in an impressive series from the Strasbourg group furtherhelps to eliminate this misconception. Page 2588
Pathophysiology of Renal Disease and Progression Delayed DMSO Administration Protects the Kidney from Mercuric Chloride-Induced Injury Nephrotoxic Kidney Injury: Can the Cat be Put Back in the Bag?
Nephrotoxic kidney injury modelsare well studied, with several protective schemes describedin animal and cellular models. The application of these approachesto acute kidney disease in humans has, however, been disappointing.The more common clinical scenario involves a patient with acutekidney disease due to nephrotoxic insults rather than consultationsrequesting help with preventative strategies. The paper by Staret al., explores the apparent beneficial effect of dimethylsulfoxide in an established animal model of nephrotoxic renalinjury in rats. The beneficial effect was seen during a vulnerablewindow of approximately 5 hours following the kidney injury,and was much less effective after that window. The beneficialeffect appears related to the anti-oxidant effects of DMSO ratherthan any direct interaction with the mercuric ion, per se. Anti-oxidanttherapy seems rational in acute kidney injury but much workremains to define the optimal approaches in human subjects.Page 2648
Basic Transplantation Ischemia-Reperfusion Induces Glomerular and Tubular Activation of Pro-Inflammatory and Anti-Apoptotic Pathways: Differential Modulation by Rapamycin Ischemia/Reperfusion Injury, DGF and Rapamycin: A Mechanistic Link?
In this manuscript Loverre et al.,studied kidney transplant recipients with delayed graft function(DGF), a clinical manifestation of ischemia/reperfusion injuryas well as an experimental model of ischemia/reperfusion inpig kidneys to highlight three interesting findings:
The coagulation cascade may play a pathogenetic role in thisinjury.
NIK activation in ischemia/reperfusion representsa pro-inflammatory,rapamycin-insensitive signal.
Akt axisis activated following ischemia/reperfusion injuryand its inhibitionmay explain prolonged DGF observed in rapamycin-treatedpatients.
These observations provide a mechanistic link at the cellularand molecular level between published observations indicatingthat in some circumstances rapamycin may prolong DGF. Page 2675
Long-Term Effects of In Utero Exposure to Cyclosporine A on Renal Function in the Rabbit Maternal Exposure to Cyclosporine Affects Offspring’s Renal Structure and Function.
In this manuscript Tendron et al.,used a rabbit model of maternal exposure to cyclosporine duringpregnancy to show that cyclosporine causes a permanent reductionin nephron mass; glomerular, tubular and intrarenal hemodynamicsdysfunction; enlarged kidneys with numerous tubular and glomerularlesions; and, an endothelin-dependent systemic hypertensionthat worsened with age. The results indicate that in utero exposureto calcineurin inhibitors induces a nephron reduction, whichled to systemic hypertension and progressive chronic renal insufficiencyin adulthood. (see editorial by Armenti et al., page 2759).Page 1687
CLINICAL SCIENCE
Clinical Nephrology Impact of an Exercise Program on Arterial Stiffness and Insulin Resistance in Hemodialysis Patients Physical Exercise - Not Only of Benefit to the Nephrologist, But Also to the Renal Patient.
It has been increasingly recognizedthat in renal patients the cardiovascular risk is increased,amongst others, by premature aging and reduced elasticity ofcentral vessels, indicated to the clinician by increased bloodpressure amplitude. Why is such increased BP amplitude deleterious?It is associated with increased peak systolic pressure, peakLV wall stress and oxygen demand on the one hand, and low diastolicpressure, low coronary perfusion and oxygen supply on the otherhand. In this issue Mustafa et al report on subjecting renalpatients to a not too strenuous aerobic exercise program. Thisfailed to affect insulin resistance (presumably because of themodest intensity of physical exercise). Yet, as assessed bypulse waveform analysis, aortic elasticity improved. A roleof sodium and angiotensin II in reducing elasticity has beenfirmly established, but -because the cardiovascular risk ofrenal patients is so enormous - any further addition to thetherapeutic armamentarium of the nephrologist is welcome. Page2713
Human Genetics A Genome Scan for End-Stage Renal Disease in African-American Families Enriched for Non-Diabetic Nephropathy A Genetic Roadmap for Hypertensive ESRD.
Hypertensive nephrosclerosis isthe second most common cause of end-stage renal disease (ESRD)in the United States and disproportionately affects African-Americans.Moreover, African-Americans who have a close relative requiringdialysis or transplantation have a greatly increased risk ofdeveloping ESRD. These observations indicate that hypertensiveESRD has a strong genetic component, but the genes that confersusceptibility have not been identified. Barry Freedman andcolleagues at Wake Forest University conducted the largest linkagestudy of ESRD to date. They analyzed 264 African-American familieswith at least one pair of siblings with non-diabetic ESRD. Usingtwo different statistical methods, they identified linkage tospecific regions on chromosomes 1, 6, 9, and 13. The evidencefor linkage was particularly strong among those with early onsetdisease and increased BMI. Although these results need to bereplicated in an independent population, they provide a roadmapfor identifying the specific ESRD-susceptibility genes. Page2719
