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Pathophysiology of Renal Disease and Progression |
* Laboratory of Nephrology; Nephrology Service; Department of Medicine, Pathology Service, IDIBELL-Hospital Universitari Bellvitge, University of Barcelona, Barcelona, Spain
Address correspondence to: Dr. Josep M. Cruzado, Nephrology Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Catalonia, Spain. Phone: +34-93-2607602; Fax: +34-93-2607607; E-mail: 27541jcg{at}comb.es
Received for publication May 26, 2005. Accepted for publication March 2, 2006.
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Abstract |
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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. |
Introduction |
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-smooth muscle actin (-SMA) expression and matrix overproduction, is considered a major feature of diabetic nephropathy (3). Histologically, diabetic nephropathy is characterized by an early thickening of tubular and glomerular basement membranes, as a result of an excessive accumulation of ECM, leading to progressive scarring and fibrosis of the kidney (4–6). Utimura et al. (7) reported the beneficial effect of the immunosuppressant mycophenolate mofetil (MMF) in preventing the progression of diabetic nephropathy. The authors suggested that these intriguing results are related to glomerular anti-inflammatory and antiproliferative effects of MMF. Sirolimus (SRL), or rapamycin, is a potent new immunosuppressant that is approved for clinical use in human transplantation (8). SRL binds with FK-binding protein 12, and this complex inhibits the mammalian target of rapamycin (mTOR) and blocks the G1 to S transition in the cell cycle. mTOR has a regulatory effect on G1-phase cyclin-dependent kinases (CDK) and activates the 70-kD S6 protein kinase, an enzyme that is involved in modulating the level of 40D ribosomal protein S6 phosphorylation. In addition, mTOR increases the activity of the eukaryotic initiation factor 4E (eIF4E) through phosphorylation and inactivation of its inhibitor, eIF4E-binding protein. The 70-kD S6 protein kinase and eIF4E are pivotal in translation initiation, which is required to accelerate the rate of protein synthesis in preparation for cell division (9). Inhibition of translation initiation by mTOR is thought to be the main mechanism of the antiproliferative effect of SRL.
There is a body of evidence about the role of CDK and their inhibitors p27Kip1 and p21Cip in diabetic nephropathy (10). Lack of those inhibitors (knockouts) protects the kidney from developing diabetic lesions in streptozotocin (STZ)-induced diabetic mice (11,12). mTOR blockade, in theory, could increase CDK inhibitors (13). Therefore, SRL hypothetically could aggravate diabetic nephropathy. However, recent data show the importance of phosphatidylinositol 3-kinase (PI3-K)/Akt/mTOR/eIF4E and 70-kD S6 pathways in diabetic nephropathy. In fact, high glucose induces mesangial hypertrophy by the Akt/mTOR pathway (14), increasing both p-Akt and mTOR in rat diabetic kidneys (15). Growth factors such as TGF-1 induce collagen I (16) and fibronectin (17) by the PI3-K/Akt pathway. In addition, Wang et al. (18) showed that SRL, at concentrations between 10 and 1000 nM, inhibits mesangial proliferation derived from PDGF. Lock et al. (19) demonstrated that low-dose SRL (0.1 to 0.001 ng/ml) has no proapoptotic effect but inhibits mesangial cell proliferation and collagen IV production. Zhang et al. (20) confirmed that SRL blocked laminin synthesis that was induced by high glucose in mesangial cells.
To assess the potential role of mTOR blockade on diabetic nephropathy in vivo, we performed a study in STZ-induced diabetic rats with diabetic kidney disease. We treated the animals with low-dose SRL and observed that it slowed the progression of diabetic nephropathy by reducing renal p-Akt, glomerular -SMA-positive cells, and ECM accumulation. These effects were produced without modification of the number of infiltrating macrophages.
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Materials and Methods |
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Induction of Diabetes and Insulin Administration
Diabetes was induced by intravenous injection of STZ (Sigma, St. Louis, MO) at 60 mg/kg body wt in 0.01 M citrate buffer (pH 4.5) after 12 h of food deprivation. Three days after STZ administration and twice a week thereafter, the rats were weighed, and tail-vein blood glucose was determined by Glucocard (Menarini, Barcelona, Spain). Insulin (Insulatard NPH, NovoNordisk (Bagsvaerd, Denmark); 1 to 5 U/d, subcutaneously) was initiated 7 d after administration of STZ to maintain blood glucose between 350 and 500 mg/dl and to avoid ketosis.
Study Groups and Renal Function
Diabetes was induced in 20 rats. Sixteen weeks after diabetes induction, animals were divided into three groups, as follows: diabetic animals that continued with blood glucose between 350 and 500 mg/dl (D; n = 8); diabetic animals that continued with blood glucose between 350 and 500 mg/dl with administration of SRL (D+SRL; 1 mg/kg per d; n = 7) by daily gavage; and diabetic animals in which normoglycemia was induced by two subcutaneous implants of insulin (Linplant, Lin Shin Canada, Inc, Scarborough, ON, Canada; D+NG; n = 5). We included six age-matched nondiabetic rats as controls (ND). Rats were placed in metabolic cages for collection of 24-h urine specimens on day 0 (before therapeutic intervention) and on day 30. Serum (sCr; mg/dl) and urine creatinine levels were determined on an autoanalyzer (Beckman Instruments, Palo Alto, CA). Urinary albumin excretion was determined by an immunoturbidimetric method in a Nefelometer II (Dade Behring, Barcelona, Spain). After a follow-up of 30 d, rats were killed and tissue samples were processed and stored as needed.
Choosing the SRL Dose
SRL at 1 mg/kg per d dose was established after previous experiments with 3 mg/kg per d. Five diabetic rats were treated at a high SRL dose. These animals died early (1 wk) as a result of intestinal ulcers and hemorrhage, with SRL levels after 1 wk of treatment at 13 ± 1 ng/ml. Therefore, 1 mg/kg per d SRL was the dose chosen for the experiments. This low dose was well tolerated without associated mortality. SRL trough levels in blood after 1 wk of treatment at 1 mg/kg per d were 2.3 ± 0.25 ng/ml (range 1.4 to 2.9 ng/ml; EIA, Imx Analyzer, Abbott Lab, Abbott, IL).
Histologic Studies
Three to 4-µm-thick tissue sections were placed in 4% formaldehyde for paraffin embedding and subsequent staining with periodic acid-Schiff (PAS) and periodic acid-silver methenamine. Masson’s trichrome staining was used to demonstrate collagen deposition. All samples were evaluated by a pathologist who was blind to the group assignment. Mesangial expansion was evaluated in periodic acid-silver methenamine- and Masson’s trichrome-stained sections as 0 (absent), 1 (mild), 2 (moderate), 3 (severe), and 4 (severe plus glomerular sclerosis). The mean glomerular volume (MGV; 106 µl3) was evaluated in PAS sections according to the Weibel and Gómez formula (21), as described elsewhere (22). Interstitial fibrosis was estimated in PAS-stained sections on the 0 to 4 scale, as described (23). For evaluation of mesangial matrix area, 30 glomeruli that were cut at the vascular pole were randomly selected from each animal, and the extent of extracellular mesangial matrix was identified by the periodic acid-methenamine-positive area in the mesangium by using a soft imaging system (ANALYSIS; Münster, Germany). The mesangial matrix index represented the ratio of mesangial matrix area divided by the tuft area, as described (24).
Electron Microscopy
Electron microscopy was performed by retrieving tissue from paraffin blocks followed by deparaffinization and postfixation in 3% glutaraldehyde and 1% osmium tetroxide. Sections were stained with lead citrate and uranyl acetate and examined on a JEOL 1010 transmission electron microscope with a Bioscan digital imaging system (Gatan, Pleasanton, CA) and soft imaging system (ANALYSIS). The thickness of the basal membrane was measured by a validated simplified method (25).
Immunohistochemical Analyses
Primary and secondary antibodies were used as described previously by our group (23). -SMA staining was evaluated as 0 (absent), 1 (mild), 2 (moderate), and 3 (severe). Connective tissue growth factor (CTGF)-positive glomerular cells per glomerular tuft were quantified in 10 glomeruli per sample. and the index of glomerular CTGF-positive cells per sample was calculated as follows: (CTGF + glomerular cells/glomerular cells) x 100. Positive ED1 cells in kidneys were counted x40 (20 fields). All samples were evaluated blindly.
Determination of Rat Kidney Hepatocyte Growth Factor
Kidneys were homogenized in the hepatocyte growth factor (HGF) extraction buffer, as described previously (26). Total protein concentration was measured by the Bradford protein assay (Bio-Rad, Hercules, CA). HGF was determined with a specific commercially available ELISA kit (Rat HGF-EIA; Institute of Immunology, Tokyo, Japan). This rat HGF antibody does not cross-react with human HGF (27). Renal HGF concentration was expressed in ng/mg protein.
Western Blot Analysis of Akt
Renal tissue was sonicated in a lysis buffer that contained 20 mM Tris (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton, 0.1% SDS, and protease inhibitor cocktail. Protein lysates (50 µg) were separated on 7% SDS-polyacrylamide gel, transferred to a nitrocellulose membrane blocked in nonfat dry milk in Tris-buffered saline (pH 7.4) that contained 0.1% Tween 20 (TBST) for 1 h, and incubated with phospho-Akt kinase antibody (Cell Signaling Technologies, Beverly, MA; 1:500) at 4°C overnight. Then immunoblots were washed with Tris-buffered saline (pH 7.4) that contained 0.1% Tween 20 and were incubated for 1 h with the horseradish peroxidase-conjugated anti-mouse secondary antibody (1:20,000; Dako, Glostrup, Denmark). Immunoreactive bands were detected using the Super Signal West Dura Extended Duration Substrate (Pierce, Milwaukee, WI). Band intensity was measured with a scanning densitometer (model GS-800; Bio-Rad). -Actin was used as an internal loading control.
Quantification of Renal TGF-1, Proliferating Cell Nuclear Antigen, HGF, CTGF and mTOR by Real-Time PCR
RNA extraction and reverse transcription were performed as described previously (23). Tissue cDNA for TGF-1, proliferating cell nuclear antigen (PCNA), HGF, CTGF, and mTOR was amplified and quantified by real-time PCR (ABI Prism 7700; Applied Biosystems, Madrid, Spain), using the predeveloped TaqMan assay reagents method and the comparative threshold cycle method (Applied Biosystems) that were valid for our pairs of amplicons (rat TGF-1/18S, rat PCNA/18S, mTOR/18S, CTGF/18S, cmet/18S, and HGF/18S), because their amplifying efficiencies were similar (data not shown). For the PCR reaction, 2 µl of each cDNA sample was mixed with 2x TaqMan Universal PCR Master Mix and 20x target primers and probe in a total reaction volume of 25 µl. For rat HGF-PCR, 2 µl of each cDNA sample was mixed with primers and probe in a total reaction volume of 25 µl to reach a final concentration of 900 nmol/L for both forward and reverse primers and 200 nmol/L for the probe. Amplification followed the universal amplification program proposed by Applied Biosystems and described previously (23). Values of normal kidneys were pooled and used as the reference value. Results were expressed as "many fold of the unknown sample" with respect to the reference value (sham group).
Statistical Analyses
All data are presented as mean ± SEM. A t test or ANOVA for parametric values and Mann-Whitney U test or Kruskall-Wallis test for nonparametric values were used to compare group means. All P values were two-tailed, and P < 0.05 was considered statistically significant.
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1, HGF, and CTGF1, and CTGF (profibrogenic). D rats had lower HGF in kidney (D versus ND; P = 0.02). It is interesting that continuous insulin (D+NG) restored renal HGF protein (D+NG versus ND; P = 0.3) but not mRNA HGF, suggesting release of HGF from nonrenal tissue. This effect was not observed in SRL-treated animals. Renal mRNA TGF-1 was higher in D than in ND rats (P = 0.01). SRL treatment reduced its expression (D+SRL versus D; P = 0.04) more than NG did (D+NG versus D; P = 0.2) but not as much as in ND. Renal mRNA CTGF was higher in D than in the other three groups. Glomerular CTGF staining was enhanced in diabetic rats (D versus ND; P < 0.001). Both SRL and NG reduced the number of CTGF-positive glomerular cells (Figure 1).
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-SMA-Positive Cells-SMA expression was enhanced in diabetic kidneys (Figures 3 and 4). In diabetic glomeruli (D), some glomerular epithelial cells expressed -SMA (Figure 3). SRL reduced glomerular -SMA more than normoglycemia, especially in the glomerular epithelial cells. -SMA was slightly overexpressed in the interstitium of D kidneys. Both SRL and NG reduced interstitial -SMA staining (Figure 4).
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Discussion |
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Experimental and clinical data showed metabolic control as the main tool to prevent the progression of diabetic nephropathy at early stages (30). Our data showed that NG reduced hyperfiltration and microalbuminuria at the level of renal function observed in ND rats. An interesting finding was that SRL impaired weight gain in diabetic rats without affecting insulin requirements and/or diabetic control. In fact, we (31) and others (32) observed previously low body weight in SRL-treated rats. Along these lines, Um et al. (33) showed that absence of S6K1, an effector pathway of mTOR, protects against age- and diet-induced obesity in mice; this offers a potential explanation for the consistent effect of SRL on weight gain. However, whether this effect is related to SRL directly or is associated with low food consumption is not known. This metabolic consequence did not account for the beneficial action of SRL, because SRL treatment did not improve glycemic control and insulin requirements in diabetic rats. Therefore, although hyperglycemia was maintained, SRL treatment significantly improved renal function parameters in a rat model of established diabetic kidney disease.
In diabetic nephropathy, there is a two-stage mesangial growth response, with early proliferation and subsequent hypertrophy (34). Our results showed that cellular proliferation in the kidney was not enhanced several months after diabetes induction. Moreover, we found that treatment with low-dose SRL did not modify cell proliferation in diabetic kidney disease. The absence of mesangial cell proliferation several weeks after diabetes induction is consistent with previous reports (34). However, glomerular hypertrophy was significantly higher in diabetic animals, as expected. After 4 wk of treatment, neither NG nor SRL reduced glomerular hypertrophy. These results do not exclude the possibility that a more prolonged intervention would reduce glomerular hypertrophy.
Today, there is growing evidence that regulation of CDK and their specific inhibitors (10), as well as the PI3-K/Akt pathway, have an important role in the renal hypertrophy of diabetic nephropathy (14). Importantly, mTOR is involved, at least in part, in the regulation of both pathways. On the one hand, the mTOR blockade theoretically could increase CDK inhibitors (13) and aggravate diabetic nephropathy, whereas on the other hand, its effect could be beneficial because it interferes with the Akt/mTOR pathway. Indeed, in vitro studies showed that SRL inhibits mesangial cell hypertrophy (14) and ECM production (20) that is induced by hyperglycemia. Consistent with previous data (15), we found that p-Akt and mTOR increased in diabetic kidneys. It was reported previously that hyperglycemia and other stimuli such as angiotensin II activated Akt/mTOR (35). In our study, NG and especially SRL treatment attenuated Akt phosphorylation, which suggests that mTOR activation also amplifies Akt pathway activation by a positive feedback These results were consistent with a previous report from Riesterer et al. (36) in which mTOR blockade reduced Akt phosphorylation in vascular endothelial growth factor-stimulated endothelial cells. Unlike the full mortality observed in diabetic nephropathy when SRL was administered at the high dose, a low SRL dose protected the kidney. Therefore, it can be hypothesized that the SRL dose is crucial to the therapeutic effect. Lock et al. (19) showed that low-dose SRL inhibits mesangial cell collagen IV production without increasing apoptosis.
We assessed some growth factors that have a pathogenic role in diabetic glomerulopathy. We found a reduction of renal HGF and an increase in glomerular CTGF and renal TGF-1. Both TGF-1 and hyperglycemia induce CTGF upregulation in mesangial cells (2). In addition, it was found that angiotensin II, an important mediator of diabetic nephropathy, induces CTGF renal expression (37). This growth factor has an important function in ECM accumulation in diabetic nephropathy (18). However, a reduction in renal HGF contributed to unsettling the equilibrium between HGF and other profibrotic growth factors such as TGF-1 and CTGF. We recently demonstrated that human HGF gene therapy regresses glomerular sclerosis in diabetic nephropathy (38). NG restored renal HGF protein but not mRNA HGF, suggesting release of HGF from nonrenal tissues and HGF downregulation by maintained high glucose, as previously reported (39). Accordingly, SRL did not modify blood glucose and did not restore HGF. Conversely, both NG and SRL partially reduced glomerular CTGF and TGF-1, suggesting that both high glucose and the mTOR pathway have an important role in upregulation of these growth factors.
In diabetic glomeruli, mesangial cell activation, characterized by -SMA induction by growth factors, is regarded as a central event that leads to ECM accumulation. Diabetic kidneys showed -SMA-positive glomerular cells, including glomerular epithelial cells of the Bowman capsule, and renal interstitial cells, suggesting that there was some degree of epithelial to mesenchymal transition (EMT). In fact, EMT is emerging as a major pathway that leads to generation of the matrix-producing effector cells in diseased kidney (40). We found several factors for EMT in diabetic glomerulopathy, such as upregulation of TGF-1 (a major stimulus of EMT) and activation of Akt, which is involved in the loss of epithelial adhesion observed at the initial stages of EMT (41). SRL treatment reduced glomerular -SMA induction and consequently ECM accumulation in diabetic kidney. D+NG rats showed some degree of glomerular and interstitial myofibroblast staining with glomerular sclerosis. These results suggest that >4 wk of NG would be required to obtain histologic benefit.
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Acknowledgments |
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We are particularly indebted to Núria Bolaños for excellent technical support. We are grateful to Yolanda Armendariz for drug monitoring support.
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) and interstitium (
) in established diabetic nephropathy. Therefore, D and ND groups had similar numbers of ED1+ cells. Intensive insulin therapy (D+NG) was associated with a slight reduction of glomerular macrophages (aP = 0.01 versus ND), whereas SRL was not. (B) A representative image shows ED1+ cells in glomeruli and interstitium of diabetic kidney Magnification, x400.
