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Rapamycin ameliorates nephropathy despite elevating hyperglycemia in a polygenic mouse model of type 2 diabetes, NONcNZO10/LtJ.

Reifsnyder PC, Doty R, Harrison DE - PLoS ONE (2014)

Bottom Line: However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced.Rapamycin treatment also reduced body weight gain.Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT
While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it has not been tested in polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with rapamycin (14 ppm encapsulated in diet) and monitored for the development of diabetes. As expected, rapamycin treatment accelerated the onset and severity of hyperglycemia. However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced. Insulin production and secretion appeared to be inhibited, suppressing the developing hyperinsulinemia present in untreated controls. Rapamycin treatment also reduced body weight gain. Thus, rapamycin reduced some of the complications of diabetes despite elevating hyperglycemia. These results suggest that multiple factors must be evaluated when assessing the benefit vs. hazard of rapamycin treatment in patients that have overt, or are at risk for, type 2 diabetes. Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

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Effect of rapamycin on kidney glomerular morphology in NONcNZO10 mice.Untreated mice (A) show hyaline deposits, likely subendothelial, in the glomerular tuft. These deposits are greatly reduced in rapa-treated mice (B). The deposits are strongly positive for IgG in untreated mice (C), and IgG staining is greatly reduced in rapa-treated mice (D). 100 glomeruli from each mouse were scored for presence of nephritis (E) and/or hyaline thrombi deposits (F), showing quantitatively the reduction in kidney disease by rapa treatment.
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pone-0114324-g002: Effect of rapamycin on kidney glomerular morphology in NONcNZO10 mice.Untreated mice (A) show hyaline deposits, likely subendothelial, in the glomerular tuft. These deposits are greatly reduced in rapa-treated mice (B). The deposits are strongly positive for IgG in untreated mice (C), and IgG staining is greatly reduced in rapa-treated mice (D). 100 glomeruli from each mouse were scored for presence of nephritis (E) and/or hyaline thrombi deposits (F), showing quantitatively the reduction in kidney disease by rapa treatment.

Mentions: Urine albumin/creatinine ratio (ACR) increases with renal damage [22]. ACRs were significantly elevated in the untreated NcZ10 and normal in the rapa-treated mice (Table 1), indicating that rapa protects from renal damage. Foci of inflammation in the kidney were seen in all eight untreated mice assessed for kidney histology but only in 2/8 rapa-treated mice. Also, 6/8 untreated mice showed hyaline deposits in the glomeruli, while only 1/8 rapa-treated mice showed this phenotype (Figure 2A, B). These deposits stained strongly positive for IgG (Figure 2C, D). Scoring 100 glomeruli from each kidney for evidence of nephritis and/or hyaline thrombi (Figure 2E, F) showed that rapa significantly reduced the development of these abnormalities despite exacerbating hyperglycemia.


Rapamycin ameliorates nephropathy despite elevating hyperglycemia in a polygenic mouse model of type 2 diabetes, NONcNZO10/LtJ.

Reifsnyder PC, Doty R, Harrison DE - PLoS ONE (2014)

Effect of rapamycin on kidney glomerular morphology in NONcNZO10 mice.Untreated mice (A) show hyaline deposits, likely subendothelial, in the glomerular tuft. These deposits are greatly reduced in rapa-treated mice (B). The deposits are strongly positive for IgG in untreated mice (C), and IgG staining is greatly reduced in rapa-treated mice (D). 100 glomeruli from each mouse were scored for presence of nephritis (E) and/or hyaline thrombi deposits (F), showing quantitatively the reduction in kidney disease by rapa treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256216&req=5

pone-0114324-g002: Effect of rapamycin on kidney glomerular morphology in NONcNZO10 mice.Untreated mice (A) show hyaline deposits, likely subendothelial, in the glomerular tuft. These deposits are greatly reduced in rapa-treated mice (B). The deposits are strongly positive for IgG in untreated mice (C), and IgG staining is greatly reduced in rapa-treated mice (D). 100 glomeruli from each mouse were scored for presence of nephritis (E) and/or hyaline thrombi deposits (F), showing quantitatively the reduction in kidney disease by rapa treatment.
Mentions: Urine albumin/creatinine ratio (ACR) increases with renal damage [22]. ACRs were significantly elevated in the untreated NcZ10 and normal in the rapa-treated mice (Table 1), indicating that rapa protects from renal damage. Foci of inflammation in the kidney were seen in all eight untreated mice assessed for kidney histology but only in 2/8 rapa-treated mice. Also, 6/8 untreated mice showed hyaline deposits in the glomeruli, while only 1/8 rapa-treated mice showed this phenotype (Figure 2A, B). These deposits stained strongly positive for IgG (Figure 2C, D). Scoring 100 glomeruli from each kidney for evidence of nephritis and/or hyaline thrombi (Figure 2E, F) showed that rapa significantly reduced the development of these abnormalities despite exacerbating hyperglycemia.

Bottom Line: However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced.Rapamycin treatment also reduced body weight gain.Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT
While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it has not been tested in polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with rapamycin (14 ppm encapsulated in diet) and monitored for the development of diabetes. As expected, rapamycin treatment accelerated the onset and severity of hyperglycemia. However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced. Insulin production and secretion appeared to be inhibited, suppressing the developing hyperinsulinemia present in untreated controls. Rapamycin treatment also reduced body weight gain. Thus, rapamycin reduced some of the complications of diabetes despite elevating hyperglycemia. These results suggest that multiple factors must be evaluated when assessing the benefit vs. hazard of rapamycin treatment in patients that have overt, or are at risk for, type 2 diabetes. Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

Show MeSH
Related in: MedlinePlus