Glomerular abundance of nephrin and podocin in experimental nephrotic syndrome: different effects of antiproteinuric therapies

Abstract

are not yet fully clarified, it is well accepted that nephrin and podocin are involved in the development of proteinuria. The effects of early treatment with various antiproteinuric therapies on proteinuria and glomerular staining of nephrin and podocin in rats with experimental NS have not been previously studied. Proteinuria and glomerular nephrin and podocin immunofluorescence were examined in rat kidneys with adriamycin-induced NS and the effects of antiproteinuric drug therapies during 5 wk with enalapril, losartan, alone or in combination, omapatrilat, and mycophenolate mofetil on these parameters were assessed. Injection of adriamycin caused a significant increase in daily (from 21.8 Ϯ 1.4 to 983.1 Ϯ 45.8 mg/day, P Ͻ 0.01) and cumulative protein excretion (from negligible values to 22,490 Ϯ 931 mg, P Ͻ 0.001) during 5 wk. Early treatment with enalapril significantly decreased the daily (641.7 Ϯ 82.4 mg/day, P Ͻ 0.0023) and cumulative proteinuria (15,727 Ϯ 2,204 mg, P Ͻ 0.001). A similar effect, although to a lesser extent, was obtained after omapatrilat treatment: cumulative proteinuria was reduced to 18,706 Ϯ 1,042 mg, P Ͻ 0.001. In contrast, losartan treatment did not significantly influence the cumulative proteinuria that remained comparable (20,351 Ϯ 1,360 mg, P Ͼ 0.05) to that observed in untreated NS rats. Unexpectedly, when losartan was given in combination with enalapril, it abolished the beneficial effects of the latter. Pretreatment with mycophenolate mofetil exerted a moderate antiproteinuric effect, which appeared only during the last week of the experimental treatment. Nephrotic rats exhibited severe disruption of slit diaphragm structure as seen by rapid and profound loss of nephrin and podocin. Beneficial effects of enalapril, omapatrilat, and mycophenolate mofetil paralleled the preservation of nephrin, as determined immunohistochemically, and enabled prediction of significant antiproteinuric responses. Enalapril alone or in combination with losartan resulted in significant preservation of podocin. Pretreatment with enalapril, and to a lesser extent omapatrilat, is superior to losartan in reducing proteinuria in NS rats. A combination of ACE inhibitors with ANG II receptor blockers does not provide any advantageous antiproteinuric therapy in these animals. Nephrin loss is an indication of proteinuria in NS and the antiproteinuric effects of ACE inhibitors, vasopeptidase inhibitors, and mycophenolate mofetil attenuate this reduction. Not all the drugs which restore podocin reduce urinary protein in NS.adriamycin; proteinuria ADRIAMYCIN (ADR)-induced nephrotic syndrome (NS) in the rat is characterized by massive proteinuria, hypoalbuminemia, dyslipidemia, hypercoagulability, edema, and ascites formation (5,16,25,26). The common denominator of this experimental nephropathy, which mimics minimal change disease and various primary and secondary kidney diseases such as diabetic nephropathy, systemic lupus erythematosus and others, is glomerular dysfunction resulting in a massive proteinuria (8)....

Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy

“…33,34 Thus, one possible explanation for our discrepant results may be due to our use of ACEi at maximal dose. Although ARB has been shown to suppress renal injury in experimental CKD, 11,35 our results are in agreement with the previous observation by Nakhoul et al 36 that enalapril but not losartan reduced proteinuria in ADR rats, and that ACEi/ ARB combination did not provide advantageous antiproteinuric responses. 24,36 Similarly, Yilmaz et al 37 also reported a lack of anti-proteinuric effect with losartan in ADR rats.…”

Dendrin Location in Podocytes Is Associated with Disease Progression in Animal and Human Glomerulopathy

“…Adriamycin (ADR) nephrosis is well known as a nephrosis and FSGS model in rats [14,15]. An LPS-induced nephrosis model has been established in mice.…”

Short-term effects of soy protein diet in patients with proteinuric glomerulopathies

“…Homeostatic mechanisms are unable to cope with such urinary protein losses, and the resulting hypoalbuminemia frequently leads to edema. 1,2 The glomerular damage that is characteristic of NS can also result in urinary loss of lipids and other plasma proteins, including some of the apolipoproteins. 3 Another important feature of the NS is hyperlipidemia characterized by increased plasma concentrations of very-low-density (VLDL), intermediatedensity, low-density lipoproteins (LDL) and, as the disorder progresses, also by hypertriglyceridemia and decreased concentrations of high-density lipoproteins (HDL).…”