Combination of chronic exercise and antihypertensive therapy enhances renoprotective effects in rats with renal ablation.

BACKGROUND: We assessed the renal protective effects of treatment with moderate exercise (EX), with EX plus olmesartan (OLS), with EX plus azelnidipine (AZN), and with the three together in a rat model of chronic renal failure (CRF). METHODS: Male 5/6-nephrectomized Wistar Kyoto (WKY) rats were divided into six groups according to the following treatments for: (i) no EX (C); (ii) moderate EX with treadmill running (20 m/min for 60 min/day, 5 days/week) (EX); (iii) EX+OLS (10 mg/kg/day); (iv) EX+AZN (3 mg/kg/day); (v) EX+OLS (5 mg/kg/day)+AZN (1.5 mg/kg/day); and (vi) sham operation (S). The rats were then treated for 12 weeks. RESULTS: EX, EX+OLS, EX+AZN, and EX+OLS+AZN showed decreases in the serum creatinine (Scr), an index of glomerular sclerosis (IGS), the relative interstitial volume of the renal cortex (RIV), the number of ED-1 (monoclonal antibody) positive cells (ED1(+)) and the glomerular expression score of alpha-smooth muscle actin (alpha-SMA(+)). EX+OLS, EX+AZN, and EX+OLS+AZN blocked the development of hypertension, increased the number of Wilms' tumor-1 (WT-1) positive cells (WT1(+)); EX+OLS and EX+OLS+AZN blunted the increases in proteinuria. In particular, blood urea nitrogen (BUN), ED1(+), alpha-SMA(+), WT1(+), IGS, and RIV in the EX+OLS+AZN were the lowest among all the nephrectomized groups. CONCLUSIONS: In the results, simultaneous treatment of EX, OLS, and AZN showed renal protective effects in this rat model suggesting that the treatment may affect the macrophage infiltration to the glomerulus, the fibroblast accumulation in the glomerulus, the mesangial activation, and the podocyte differentiation.

Combination of exercise and losartan enhances renoprotective and peripheral effects in spontaneously type 2 diabetes mellitus rats with nephropathy.

OBJECTIVES: We assessed the renal and peripheral effects of chronic exercise in a rat model of diabetic nephropathy and the benefits of combined exercise and losartan. METHODS: Heminephrectomized Goto-Kakizaki rats were divided into four groups: (i) no exercise (control); (ii) exercise with treadmill running; (iii) losartan; (iv) exercise plus losartan, and the rats were treated for 12 weeks. RESULTS: Losartan and exercise plus losartan significantly decreased systolic blood pressure (SBP). Exercise, exercise and losartan, and losartan blunted the increases in proteinuria. The index of glomerular sclerosis (IGS) and the relative interstitial volume of the renal cortex were significantly improved in the exercise, exercise and losartan, and losartan groups. The IGS, expressions of ED-1 and alpha-smooth muscle actin in the glomerulus were the lowest, and the number of Wilms' tumour was the highest in the exercise plus losartan group. The endurance, the proportion of type I fibre and capillarization in the extensor digitorum longus muscle were greater in the trained groups. CONCLUSION: These results suggest that both exercise and losartan have renoprotective effects, and the combination of exercise and losartan provided greater renoprotective effects than losartan alone, and may affect macrophage infiltration, mesangial activation, and podocyte loss in this model of diabetic nephropathy. It is also suggested that exercise has a specific renoprotective effect that is not related to SBP reduction, and can enhance endurance without renal complications.

Combination of exercise and enalapril enhances renoprotective and peripheral effects in rats with renal ablation.

BACKGROUND: It is suggested that appropriate chronic exercise (EX) may produce improvements of the physical strength in patients with chronic renal failure (CRF). Because acute exercise causes proteinuria and decreases the renal blood flow and glomerular filtration rate, it is necessary to consider the influence of EX on renal function. Therefore, we assessed the renal and peripheral effects of moderate to intense EX as well as the effects of the combination of EX and enalapril (ENA) in a rat model of CRF. METHODS: Male 5/6-nephrectomized Wistar-Kyoto rats were divided into six groups according to the following treatment: 1) no exercise (C); 2) ENA (2 mg/kg/day, subcutaneously); 3) moderate exercise with treadmill running (20 m/min for 60 min/day, 5 days/week) (EXm); 4) intense exercise with treadmill running (28 m/min for 60 min/day, 5 days/week) (EXi); 5) EXm+ENA; and 6) sham operation (S). The rats were then treated for 12 weeks. RESULTS: Both EX and ENA blocked the development of hypertension, blunted increases in proteinuria, reduced serum creatinine and blood urea nitrogen, and improved the index of glomerular sclerosis (IGS) and the relative interstitial volume of the renal cortex (RIV). Moreover, IGS and RIV in the EXm+ENA group were the lowest among all other nephrectomized groups. Furthermore, EXm+ENA enhanced capillarization as well as the proportion of type-I fiber in the soleus muscle. CONCLUSIONS: These results suggest that EX and ENA have renoprotective effects. The findings also suggest that EXm+ENA provided greater renoprotective effects than those of ENA alone, and that EXm+ENA had some additional peripheral effects without any complications in this rat model.

The involvement of advanced glycation endproducts (AGEs) in renal injury of diabetic glomerulosclerosis: association with phenotypic change in renal cells and infiltration of immune cells.

BACKGROUND: Glycation of proteins is regarded as one of the major causes of the progression of diabetic nephropathy (DN) and of the phenotypic changes in glomerular mesangial cells (MC) and the cellular infiltration that occurs in MC from DN. It thus is very important to study the interrelationships and interaction between these causes. METHODS: The localization of advanced glycation endproducts (AGEs), cytoskeletal proteins, and immune cell infiltration was evaluated by immunohistochemical study in patients with DN. RESULTS: N(Epsilon)-(carboxymethyl)lysine (CML), Alpha-smooth muscle actin (SMA), and low-molecular-weight caldesmon (L-CLD) were localized in the mesangial area in DN. The intensity of mesangial SMA and L-CLD expression was significantly correlated with the index of diabetic glomerulosclerosis (IDGS), while the expression of pentosidine was correlated with the IDGS and with 24-h urinary protein. Pentosidine was localized in glomerular basement membrane (GBM) only in DN and had a significant correlation with the mesangial expression of SMA and L-CLD. Pyrraline deposition on the tubular basement membrane, and the expression of SMA and L-CLD, and the infiltration of immune cells were observed in interstitial areas in DN. The intensity of L-CLD expression had a close relationship with pyrraline deposition and immune cell infiltration. The expression of SMA and L-CLD in interstitial areas was significantly correlated with the percent interstitial volume. CONCLUSIONS: AGEs are involved in renal injury in DN, and their effect is, at least in part, exercised via phenotypic changes in intrinsic renal cells and by the infiltration of immune cells.

Phenotypic change of glomerular podocytes in primary focal segmental glomerulosclerosis: developmental paradigm?

WT1 and Pax2 are transcription factors involved in kidney development and phenotypic regulation of glomerular epithelial cells. In primary focal segmental glomerulosclerosis (FSGS), the alteration of the podocyte is important for the development of the cellular lesion (CL) and glomerular scar formation. To investigate the contribution of WT1 and Pax2 to the development of the CL in primary FSGS, immunohistological studies were performed using renal biopsy specimens on the expression of WT1, Pax2 and cytokeratin (CK), which is an epithelial marker but never found in normal podocytes. The expression of WT1 was decreased in the CL compared with unaffected podocytes, but Pax2 and CK were expressed significantly in the CL and also in the cells morphologically recognized as podocytes in cases with CL. Our results suggest that re-expression of Pax2 resulting in phenotypic change of podocytes to a different epithelial form is important for the development of the CL in primary FSGS. Normal podocytes resemble mesenchymal cells since they express both vimentin and WT1. In contrast, epithelial cells including parietal epithelial cells of the Bowman's capsule express both Pax2 and CK. Therefore, the mechanism of phenotypic change of podocytes in the CL in primary FSGS might be mesenchymal-epithelial transformation and a developmental paradigm.

Significance of early phenotypic change of glomerular podocytes detected by Pax2 in primary focal segmental glomerulosclerosis.

In primary focal segmental glomerulosclerosis (FSGS), phenotypic alteration of podocytes is important for the development of cellular lesions (CLs), which precede glomerular scar formation. WT1 and Pax2 are transcription factors involved in kidney development and phenotypic regulation of glomerular epithelial cells. However, the role of WT1 and Pax2 in the development of CLs in primary FSGS is unclear. Using immunohistochemistry, the expression of WT1, Pax2, and cytokeratin (CK), an epithelial marker never found in normal podocytes, was examined in 35 biopsy samples of primary FSGS. Segmental lesions were categorized as: (1) classic segmental scar (CS), (2) CL, and (3) monolayer epithelial (ME) lesion. In normal glomeruli, WT1 was strongly positive in podocytes and weakly positive in parietal epithelium of Bowman's capsule. Pax2 was strongly positive in parietal epithelium of Bowman's capsule, but never expressed in podocytes. Expression of WT1, Pax2, and CK was scantly positive in CSs. WT1 expression was decreased in CLs compared with unaffected podocytes, but Pax2 and CK were strongly expressed in CLs and podocytes of morphologically unaffected tufts in cases with CLs. WT1 expression was strong, as well as Pax2 and CK, in ME lesions. Clinically, urinary protein levels were significantly greater, and the interval from clinical onset to biopsy was significantly shorter in patients with CLs. These results suggest that re-expression of Pax2 in podocytes resulting in phenotypic change to a different epithelial form is one of the important changes for the development of CLs and ME lesions. Alteration from WT1 to Pax2 in podocytes may have an important role in the initiation of glomerular injury in primary FSGS.