Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury.

Blockade of angiotensin (Ang) II is efficient in various renal diseases. Although interest has focused on the hemodynamic changes and reduction of proteinuria, recent studies emphasize the nonhemodynamic effects of Ang II on kidney injury. The aim of this study was to clarify the mechanisms of Ang II on the immune system that alter the balance of helper T-cell (Th) subsets.

Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model.

Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on the premises that these drugs have an added protective effect beyond their influence on BP. The present study used a strain of spontaneously hypertensive/NIH-corpulent rats [SHR/NDmc-cp (fat/fat)] as a model of type II DN to unravel the renoprotective effects of anti-hypertensive drugs. Olmesartan (1 or 5 mg/kg per d), an ARB, and hydralazine (5mg/kg per d), an anti-hypertensive drug without effect on the renin-angiotensin system (RAS), were given for 20 wk.

Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis.

Background: The pathogenesis of restless legs syndrome (RLS) is still unclear. The purpose of this study is to determine relationships of the presence of RLS in uremic patients regularly undergoing hemodialysis (HD) with demographic, clinical, and psychological factors.

Methods: In 490 uremic patients on HD therapy in Japan, RLS was diagnosed based on diagnostic criteria established by the International Restless Legs Syndrome Study Group.

Affinity adsorption of glucose degradation products improves the biocompatibility of conventional peritoneal dialysis fluid.

Background: Reactive carbonyl compounds (RCOs) present in peritoneal dialysis (PD) fluid have been incriminated in the progressive deterioration of the peritoneal membrane in long-term PD patients. They are initially present in fresh conventional heat-sterilized glucose PD fluid and are supplemented during dwell time by the diffusion of blood RCOs within the peritoneal cavity. In the present study, RCO entrapping agents were immobilized on affinity beads to adsorb RCOs both in fresh PD fluid and in PD effluent.

Transcriptional regulation of a mesangium-predominant gene, megsin.

The cDNA of a new human mesangium-predominant gene, megsin, a novel member of the serpin superfamily, has recently been cloned. This study investigates the regulatory mechanisms of megsin gene expression. A genomic clone of the human megsin gene was obtained by screening bacterial artificial chromosome (BAC) library with the megsin cDNA.

Contribution of genetically engineered animals to the analyses of complement in the pathogenesis of nephritis.

The complement system is indispensable for host defence. Unregulated activation, however, is related to various diseases. In order to elucidate the significance of complement, methodology that disrupts the complement system is essential.

Mesangial cell-predominant gene, megsin.

We identified a novel gene, termed megsin, predominantly expressed in mesangial cells utilizing a 3'-directed regional cDNA library from cultured human mesangial cells. Megsin is a novel serine protease inhibitor (serpin), and the level of megsin RNA/protein expression is up-regulated in patients with IgA nephropathy or diabetic nephropathy, suggesting a link between megsin expression and the pathogenesis of mesangial expansion and/or proliferation. To assess the pathophysiological significance of megsin, we produced human megsin transgenic mice.

Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms.

The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N(epsilon)-carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose.

Captopril renography in Bartter's syndrome.

We describe a 19-year-old man who developed muscle weakness due to hypokalemia. His blood pressure on admission was considered to be relatively high, and we performed captopril renography. His baseline renogram was normal, while the results of captopril renography showed delayed patterns similar to those of renovascular hypertension.

ET(B) receptor protects the tubulointerstitium in experimental thrombotic microangiopathy.

Background: The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury with thrombus formation and subsequent ischemic tubulointerstitial damage. The endothelin ET(B) receptor has been shown to mediate both endothelial cell proliferation and vasodilation, and we therefore hypothesized that blockade of this receptor might promote more severe injury in this model.

Methods: TMA was induced in recently established transgenic rats that lack expression of ET(B) receptor in the kidney; these animals were compared to control rats with TMA both in the short-term (days 1 and 3) when acute glomerular injury was most manifest, and the long-term (day 17) when glomeruli have recovered but tubulointerstitial injury is still present.

Efficient in vitro lowering of carbonyl stress by the glyoxalase system in conventional glucose peritoneal dialysis fluid.

Background: Reactive carbonyl compounds (RCOs) present in heat-sterilized peritoneal dialysis (PD) fluid have been incriminated in the progressive deterioration of the peritoneal membrane observed in long-term PD patients. The present study utilized the glyoxalase I (GLO I) system as a new approach to lower in vitro the peritoneal fluid content of RCOs such as methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG).

Methods: GO, MGO, and 3-DG solutions or conventional glucose PD fluids were incubated in vitro with various RCO lowering compounds.

In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage.

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure.

Glucose dialysate induces mitochondrial DNA damage in peritoneal mesothelial cells.

Background: It is known that peritoneal mesothelial cells (PMCs) are denuded in patients undergoing long-term continuous ambulatory peritoneal dialysis (CAPD); the mechanism of damage is not well known. A high quantity of glucose loaded onto PMCs in these patients may generate toxic radicals during the mitochondrial metabolism, leading to mitochondrial DNA damage that accumulates due to the incomplete repair system of this DNA.

Objective: To study damage to the PMCs of long-term CAPD patients, and to examine whether glucose overload accelerates this damage in vitro.

Sphingosine 1-phosphate stimulates rat mesangial cell proliferation from outside the cells.

Background: Proliferation of mesangial cells (MCs) is the initial step in glomerulonephritis, and platelet-derived mediators have been shown to play a significant role in this proliferation. Sphingosine 1-phosphate (S1P), one of the sphingolipids, is abundantly stored in platelets and is released upon stimulation. We examined the effects of S1P and related sphingolipids on the cell fate of cultured MCs in order to elucidate potential roles of these lipid mediators in glomerulonephritis.

C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys.

Although it was once considered only a marker of glomerular damage, accumulating evidence indicates that proteinuria per se is nephrotoxic and contributes to the progression of renal injury. Several studies have demonstrated that activation of complement in proteinuric urine results in tubular and interstitial damage. It was previously demonstrated that acute complement-mediated interstitial disease is induced by C5b-9.

Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion.

Mesangial cells maintain normal glomerular function by mediating ECM remodeling and immune complex disposal. We have recently identified megsin, a novel member of the serine protease inhibitor (serpin) superfamily predominantly expressed in the mesangium. While our previous studies suggested a role for megsin in the pathogenesis of human glomerular diseases, its exact biological significance remained unknown.

Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient.

Background: Advanced glycation of proteins and their attendant advanced glycation end products (AGEs) contribute to the complications associated with diabetes mellitus or uremia. Regulatory mechanisms of AGE formation in vivo remain an issue of particular interest. We investigated a role of the glyoxalase detoxification system of precursor reactive carbonyl compounds (RCOs) in the in vivo AGE formation.

Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells.

Mesangial cells play an important role in maintaining glomeruli structure and function and in the pathogenesis of glomerular diseases. With a novel approach using a rapid large-scale DNA sequencing strategy and computerized data processing, a new human gene, PP4(Rmeg) was cloned. The full-length cDNA clone of human PP4(Rmeg) coded for a novel 950-amino acid protein, which was similar to a subunit of protein serine/threonine phosphatase 4 (PP4).

Protective role of nitric oxide in a model of thrombotic microangiopathy in rats.

Anew model of thrombotic microangiopathy (TMA) was previously developed, and it was demonstrated that endothelial nitric oxide (NO) synthase (NOS) is upregulated in glomeruli in this model. It was hypothesized that the synthesis of NO, a potent vasodilator and platelet inhibitory factor, is induced as a defense mechanism. The goal of this study was to clarify the role of NO in this model.

Specific tissue distribution of megsin, a novel serpin, in the glomerulus and its up-regulation in IgA nephropathy.

Mesangial cells play critical roles in maintaining a structure and function of the glomerulus. We previously cloned a novel mesangium-predominant gene, megsin, a new serine protease inhibitor. To clarify localization and roles of megsin protein, we raised polyclonal antibodies to megsin.

Increased susceptibility of decay-accelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis.

To prevent complement-mediated autologous tissue damage, host cells express a number of membrane-bound complement inhibitors. Decay-accelerating factor (DAF, CD55) is a GPI-linked membrane complement regulator that is widely expressed in mammalian tissues including the kidney. DAF inhibits the C3 convertase of both the classical and alternative pathways.

Cloning of rodent megsin revealed its up-regulation in mesangioproliferative nephritis.

Background: We recently cloned a new human mesangium-predominant gene, megsin. Megsin is a novel member of the serine protease inhibitor (serpin) superfamily. To elucidate functional roles of this gene, we cloned megsin in rodents and investigated its role in a rat nephritis model.

Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury.

Background: Clusterin is a soluble complement regulatory protein that binds to C5b-7 and inhibits generation of membrane attack complex, C5b-9. Glomerular deposition of clusterin has been observed in human and experimental membranous nephropathy in association with C5b-9 and immune deposits. However, it is controversial as to whether clusterin observed in glomeruli is synthesized by the resident glomerular cells or is derived from the circulation.