Mammalian Target of Rapamycin Pathway Blockade Slows Progression of Diabetic Kidney Disease in Rats

Abstract

Recent data suggest that the phosphatidylinositol 3-kinase (PI3-K)/Akt/mammalian target of rapamycin (mTOR) pathway is important in diabetic nephropathy. The effect of mTOR blockade by sirolimus (SRL) in diabetic kidney disease in rats was investigated. Diabetes was induced by streptozotocin in male Sprague-Dawley rats. Sixteen weeks later, diabetic animals were divided into the following groups: diabetes (D; n ‫؍‬ 8), diabetes ؉ SRL at 1 mg/kg per d, SRL trough level 2.3 ؎ 0.25 ng/ml (D؉SRL; n ‫؍‬ 7); and diabetes ؉ normoglycemia maintained by insulin implants (D؉NG; n ‫؍‬ 5). There was an age-matched nondiabetic group (ND; n ‫؍‬ 6). All animals were followed for 4 wk. The D group showed glomerular hypertrophy (mean glomerular volume 5.0 ؎ 0.4 in D versus 3.3 ؎ 0.2 10 6 3 in ND; P < 0.05) without renal hyperplasia (calculated by reverse transcription-PCR of proliferative cell nuclear antigen) and albuminuria (29 ؎ 4 in D versus 1.4 ؎ 1.5 mg/24 h in ND; P < 0.05). Both D؉NG and D؉SRL groups had a significant reduction of albuminuria, although glomerular hypertrophy was still present. SRL treatment did not modify the number of infiltrating renal ED1 ؉ cells. Diabetic animals had greater expression of p-Akt and mTOR, unlike ND rats. NG and SRL treatment reduced p-Akt and normalized mTOR. It is interesting that D؉SRL was associated with a significant reduction of renal TGF-␤1 and glomerular connective tissue growth factor. SRL treatment reduced glomerular ␣-smooth muscle actin overexpression and reduced significantly the mesangial matrix accumulation that is characteristic of diabetic nephropathy. In conclusion, mTOR blockade by low-dose SRL has a beneficial effect in diabetic kidney disease, suggesting that the mTOR pathway has an important pathogenic role in diabetic nephropathy.

Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

“…It is imaginable that VEGF might be needed for endothelial repair for a short period and later exert negative effects in terms of favoring glomerular hypertrophy and fibrotic mechanisms. However, the implication of the VEGF system in different models of disease such as the model of antiThy1.1 nephritis 23 or of diabetic nephropathy 20 or ours might be different and not sufficient to explain the distinct effects of mTOR-I treatment in these different models or in transplant patients.…”

“…We could further show that sirolimus treatment was accompanied by less interstitial inflammation and fibrosis, less tubular atrophy, and less glomerular lesions after 3 mo of treatment. In a rat model of type 1 diabetes with diabetic nephropathy, Lloberas et al 20 demonstrated the beneficial effects of sirolimus treatment. They showed that low-dosage treatment with trough concentrations of 2.3 ng/ml led to significantly decreased albuminuria.…”

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

“…The beneficial effects of mTOR inhibition have recently been reported in several rat models of chronic kidney disease, i.e., hypertensive 5 ⁄6 nephrectomy, diabetic nephropathy, hypertrophy following unilateral nephrectomy, tubulointerstitial fibrosis due to urethral obstruction or nephrotic syndrome, and polycystic kidney disease (2,5,10,19,26,29). These beneficial results are now expanded toward a progressive model of human mesangioproliferative nephropathy as a leading cause of end-stage kidney disease worldwide (13,14).…”

mRNA Translation

“…High glucose augments TGF-␤ mRNA in proximal tubular epithelial cells; successful translation of TGF-␤ mRNA into protein, however, depends on PDGF (105). Recently, Lloberas et al (106) reported that administration of rapamycin to rats with streptozotocininduced type 1 diabetes resulted in reduction in TGF-␤ mRNA expression, mesangial matrix expansion, and albuminuria but not glomerular hypertrophy.…”