Rapamycin Reduces Proteinuria and Renal Damage in the Rat Remnant Kidney Model

Esposito, Ciro; Villa, Luigi; Grosjean, Fabrizio; Mangione, Filippo; Esposito, Vittoria; Castoldi, Francesca; Serpieri, Nicoletta; Arra, Mariarosa; Pertile, Enrico; Maggi, N; Valentino, Rossella; Canton, Antonio Dal

doi:10.1016/j.transproceed.2009.04.005

Cited by 9 publications

(4 citation statements)

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“…In support of this notion, oral administration of rapamycin, a compound that increases mouse lifespan and inhibits mTOR signals downstream of IGF-1 (Harrison et al, 2009), has been shown to inhibit progression of anti-thy1-induced glomerulosclerosis in rats (Krämer et al, 2008). These effects of rapamycin on glomerulosclerosis, and other forms of kidney pathology (Bonegio et al, 2005; Diekmann et al, 2007; Esposito et al, 2009), appear related to inhibition of the IGF-1 / mTOR pathway at the local tissue level, without alternation of endocrine GH / IGF-1 signals. Taken together, these observations suggest that glomerulosclerosis could be among age-associated pathologies attenuated in PappA (−/−) mice, and that such effects may be shared among long-lived mutants carrying GH / IGF-1 endocrine mutations, and possibly rapamycin-treated mice as well.…”

Section: Discussionmentioning

confidence: 98%

In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene

Masternak

Bartke

2010

Experimental Gerontology

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Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the PappA(−/−) mouse, and whether effects of this mutation parallel those of mutations that diminish IGF-1 in serum. Across a panel of 21 tissues, we used RT-PCR to evaluate the effects of the PappA(−/−) mutation on expression of Igfbp5, which served as an in vivo indicator of IGF-1 signaling. Among these tissues, expression of Igfbp5 was significantly reduced by PappA(−/−) only in kidney. A broader survey of IGF-associated genes in six organs identified five other genes responsive to PappA(−/−) in kidney, with stronger effects in this organ relative to other tissues. Renal expression of Irs1 and Mt1 was increased by PappA(−/−) as well as by mutations that reduce IGF-1 in serum (i.e., Ghr(−/−), Pit1(dw/dw) and Prop1(df/df)), and we demonstrate that expression of these genes is regulated by growth hormonetreatment and calorie restriction. These results provide in vivo data on an important new model of mammalian aging, and characterize both similar and contrasting expression patterns between longlived mice with reduced local IGF-1 availability and diminished IGF-1 in serum.

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Section: Discussionmentioning

confidence: 98%

In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene

Masternak

Bartke

2010

Experimental Gerontology

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“…Although mTORi is well known for inducing severe proteinuria clinically [6,7], only a few reports explain how proteinuria is triggered by mTOR inhibition [7]. Recently, Stallone et al [8] reported that RPM decreased slit diaphragm (SD)-associated molecules dose-dependently; however, they did not show the direct causation between them, and only some patients with the use of mTORi had podocyte injury clinically.…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Analysis of Rapamycin Versus Cyclosporine Combination Treatment in Mouse Podocytes

Kim

Cho

Lee

et al. 2016

Transplantation Proceedings

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“…Because CRF, especially that induced by 5/6 nephrectomy, 39,40 is frequently associated with proteinuria, another hypothesis to explain the observed calcidiol deficiency is an increase in urinary losses of calcidiol. [41][42][43] We thus measured the levels of 25(OH)D 3 in urine of control rats and rats with CRF.…”

Section: Discussionmentioning

confidence: 99%

Reduced Hepatic Synthesis of Calcidiol in Uremia

Naud

Ouimet

et al. 2010

Journal of the American Society of Nephrology

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Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D 3 C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P Ͻ 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D 3 or 1␣-hydroxyvitamin D 3 , respectively, suggesting impaired C-25-hydroxylation of vitamin D 3 . Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms. ] deficiency has also been demonstrated in patients with stages 3 and 4 chronic kidney disease (CKD) and in patients who are on dialysis. [1][2][3][4][5][6][7][8] In fact, low serum 25(OH)D 3 is so intimately associated with CRF that in one study, only 29 and 17% of patients with stages 3 and 4 CKD, respectively, had sufficient levels [defined as a serum 25(OH)D 3 concentrations Ͼ75 nmol/L or 30 ng/ml]. 2 A more recent study showed a prevalence of calcidiol insufficiency and deficiency as high as 98% in predialysis patients with a mean GFR of 18.3 ml/min. 4 Prevalence of low serum 25(OH)D 3 was 78 and 89% in two large cohorts of hemodialysis patients 9,10 and 87% in a large cohort of peritoneal dialysis patients. 11 The metabolic consequences of calcidiol defi-

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Rapamycin Reduces Proteinuria and Renal Damage in the Rat Remnant Kidney Model

Cited by 9 publications

References 10 publications

In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene

In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene

Comparative Proteomic Analysis of Rapamycin Versus Cyclosporine Combination Treatment in Mouse Podocytes

Reduced Hepatic Synthesis of Calcidiol in Uremia

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