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Limiting enteric sodium absorption is an attractive option when renal sodium excretion is disturbed. An effective approach in the gut appears to be inhibition of the electroneutral Na(+)/H(+) exchangers (NHE), in particular NHE3. Recently, fluid retention, blood pressure and target organ injury were limited in rats with cardiorenal syndrome when treated with the NHE3 inhibitor tenapanor. The downside was that the osmotic fecal load leads to watery feces. Tenapanor also induced marked reductions in enteric phosphorus absorption in rats with cardiorenal syndrome on a high phosphorus intake and resulted in marked reductions in renal injury and practically prevented vascular calcification. We have yet to discover the clinical relevance in volume terms and vascular calcifications in patients in relation to the tolerated dose. However, even if the tenapanor-induced reduction in sodium adsorption is limited in humins, combination of tenapanor therapy with diuretics may be an interesting option in selected patients.

Female Nagase analbuminemic rats (NAR) are profoundly hypertriglyceridemic and develop proteinuria and glomerulosclerosis when aging and after uninephrectomy (UNX). Ovariectomy (OVX) markedly decreases plasma triglyceride levels in this species. This study evaluated whether decreasing triglyceride levels by OVX could prevent renal disease or alleviate its progression in UNX female NAR. Female NAR underwent OVX at 0, 12, 24, or 36 wk after UNX. In the absence of OVX, the animals developed progressive proteinuria from 18 wk after UNX and showed extensive glomerular sclerosis, lipid deposition, and hypertrophy at euthanasia (49 wk after UNX). These changes were prevented by OVX carried out at 0 or 12 wk, and attenuated by OVX at 24 wk after UNX. If performed at 36 wk after UNX, OVX had no effect on glomerulosclerosis, although it reduced proteinuria. In 95% (20 of 21) of the rats with proteinuria over 10 mg/day, proteinuria decreased in the first 6 wk after OVX. The percentage decrease in proteinuria correlated inversely with the glomerulosclerosis score at euthanasia (r = -0.58, P

BACKGROUND: Male rats are generally more prone to developing renal disease than female rats. However, female Nagase analbuminemic rats (NAR) are profoundly hyperlipidemic and develop proteinuria and glomerulosclerosis after uninephrectomy. Male NAR are less hyperlipidemic and are resistant to developing renal damage after uninephrectomy. Ovariectomy markedly decreases hepatic triglyceride secretion and plasma triglyceride levels in the female NAR. EXPERIMENTAL DESIGN: In this study, we investigated the relationship between plasma lipids and lipoprotein composition as well as the development of proteinuria, glomerular apolipoprotein and lipid deposition, and glomerulosclerosis in aging female and male analbuminemic rats. We also studied whether ovariectomy in female NAR at an early age would protect their renal function in old age. RESULTS: Aging hyperlipidemic female NAR with high triglyceride and cholesterol levels in very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) were found to develop spontaneous proteinuria at 9 months of age. Glomerular lipid deposition and glomerulosclerosis were observed at 18 months of age. In male NAR that had lower lipid levels in VLDL and IDL, only mild proteinuria and no glomerular lipid deposition or glomerulosclerosis were observed up to the age of 22 months. Concurrently ovariectomized NAR demonstrated profound and persistent decreases in triglyceride and cholesterol content of VLDL and IDL as well as total plasma triglycerides, without much change in LDL, high density lipoprotein, total plasma cholesterol, or apolipoprotein B, and they remained completely free of proteinuria and glomerulosclerosis. Apolipoprotein B deposition in glomeruli was not different in the oldest female, male, or ovariectomized NAR No important differences were observed in glomerular diameter between the three different groups up to the age of 1 year. CONCLUSIONS: These findings point to an important role of elevated lipid content of the triglyceride-rich lipoproteins VLDL and IDL in the pathogenesis of proteinuria and glomerulosclerosis in the female NAR.

Recent experimental data suggest a role for lipids in the pathogenesis of glomerulosclerosis. In this study, we examined the main apolipoproteins (apo) of high density lipoproteins (A-I, A-IV, E), low density lipoproteins (B), and very low density lipoproteins (B, E) in plasma and kidney tissue of rats with puromycin aminonucleoside or adriamycin nephrosis. In full-blown nephrosis, plasma concentrations of apo A-I and apo B were significantly elevated, apo A-I and apo E levels did not change. Immunohistological studies in plastic sections retreated increased apo A-I, apo A-IV, and apo E immunoreactivity in glomerular visceral epithelial cells both in puromycin aminonucleoside and adriamycin nephrosis. This was confirmed by immunoelectronmicroscopy. In addition, apo B and apo E were encountered in increased amounts in the mesangium and co-localized with Oil Red O-positive lipid deposits, particularly in puromycin aminonucleoside nephrosis rats. Double-staining showed a preferential localization of apo B and apo E at sites of increased mesangial matrix in close proximity to ED1-positive foam cells, i.e., the mesangial macrophages. The close topographic association between apo B and apo E, lipid deposits, and macrophages in the mesangium lend further support to the concept of lipid-mediated glomerular injury in nephrosis.

The albuminuria occurring after swimming in splenectomized dogs was investigated. Swimming in splenectomized dogs induces metabolic acidosis, a decrease in renal vascular conductance, and an increase in plasma renin activity, all three factors possibly implicated in the occurrence of albuminuria. The administration of sodium bicarbonate prior to swimming reduced the magnitude of the acidosis and eliminated the increase in albuminuria after swimming. Phenoxybenzamine, an alpha-adrenergic blocking agent that maintains the renal blood flow during exercise also blocked the increase in albuminuria despite a decrease of blood pH during swimming. However, after metoprolol, a beta 1-adrenergic blocking agent that blocks the rise in plasma renin activity during exercise, swimming causes a threefold increase in albuminuria (P less than 0.01). The albuminuric response to swimming preceded by saline was also significant (P less than 0.05). It is likely that post-swimming albuminuria in splenectomized dogs is linked to the decrease of renal vascular conductance or to the decrease in blood pH rather than to the rise in plasma renin activity.

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.