Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Russo, Leileata M.; Re, Elisabetta C. del; Brown, Dennis; Lin, Herbert Y.

doi:10.2337/db06-1018

Cited by 112 publications

(90 citation statements)

References 53 publications

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“…The hypertrophy of the kidney in the diabetic rat was associated with a marked increase in the urinary excretion of TGF-␤, a factor that is involved in growth and proliferation and cellular differentiation and which has been implicated in some of the renal manifestations of diabetes (26,28). Increased TGF-␤ gene expression has been reported for the BB rat and the NOD mouse, models of type 1 diabetes (29), and TGF-␤ protein expression was increased in glomeruli from a patient with diabetes (30).…”

Section: Discussionmentioning

confidence: 99%

Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats

Santos

Pedraza

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Quilley J, Santos M, Pedraza P. Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats. Am J Physiol Heart Circ Physiol 300: H2316 -H2322, 2011. First published March 25, 2011 doi:10.1152/ajpheart.01259.2010.-The induction of renal cyclooxygenase-2 (COX-2) in diabetes has been implicated in the renal functional and structural changes in models where hypertension or uninephrectomy was superimposed. We examined the protective effects of 3 mo treatment of streptozotocin-diabetic rats with a highly selective COX-2 inhibitor (SC-58236) in terms of albuminuria, renal hypertrophy, and the excretion of TNF-␣ and TGF-␤, which have also been implicated in the detrimental renal effects of diabetes. SC-58236 treatment (3 mg·kg Ϫ1 ·day Ϫ1 ) of diabetic rats resulted in reduced urinary excretion of PGE2, 6-ketoPGF1␣, and thromboxane B 2, all of which were increased in the diabetic rat compared with age-matched nondiabetic rats. However, serum thromboxane B2 levels were unchanged, confirming the selectivity of SC-58236 for COX-2. The renal protective effects of treatment of diabetic rats with the COX-2 inhibitor were reflected by a marked reduction in albuminuria, a reduction in kidney weight-to-body weight ratio, and TGF-␤ excretion and a marked decrease in the urinary excretion of TNF-␣. The protective effects of SC-58236 were independent of changes in plasma glucose levels or serum advanced glycation end-product levels, which were not different from those of untreated diabetic rats. In an additional study, the inhibition of COX-2 with SC-58236 for 4 wk in diabetic rats resulted in creatinine clearance rates not different from those of control rats. These results confirm that the inhibition of COX-2 in the streptozotocin-diabetic rat confers renal protection and suggest that the induction of COX-2 precedes the increases in cytokines, TNF-␣, and TGF-␤. cyclooxygenase-2 inhibition; kidney THERE HAVE BEEN NUMEROUS REPORTS of increased renal cyclooxygenase (COX) activity and prostaglandin production in diabetes (10, 27), which has been linked to hyperfiltration (8, 21) that precedes renal structural changes and the development of nephropathy (13,22), although the cause and effect is not unequivocally established. Before the recognition of different COX isoforms, there were some studies linking altered renal arachidonic acid (AA) metabolism to the development of nephropathy by showing that NSAIDs exerted renal protective effects in diabetes (21). Following the discovery of multiple COX isoforms, it was shown that experimental diabetes results in the upregulation of renal COX-2 (17). We confirmed the increase in renal COX-2 in the diabetic rat and showed an association with enhanced prostaglandin release from the perfused kidney challenged with AA, which serves as an index of COX activity but does not distinguish the COX isoforms (24). Nonetheless, our studies have shown that interventions that prevent the upregulation of renal COX-2 in the diabetic rat are, for the most part, associa...

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Section: Discussionmentioning

confidence: 99%

Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats

Santos

Pedraza

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…In support of this, Ang II has been shown to induce marked glomerular sclerosis 27 with cell proliferation of the glomerular mesangium, 28 vascular endothelium, 29 tubular epithelium 30 and the vascular smooth muscle. 31 Ang II causes podocyte injury by increasing glomerular capillary pressure through a selective constriction of efferent arterioles. 32,33 In addition, Ang II is thought to act directly on podocytes.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

et al. 2009

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Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg À1 per day, p.o.) or ARB (olmesartan, 5 mg kg À1 per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-b mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

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“…3). Decreased megalin expression in PTCs has been observed in the early diabetic stages of experimental animals (Tojo et al 2001;Russo et al 2007), and it has been suggested that the functions of megalin are also impaired in patients during the early stages of diabetic nephropathy, since low molecular weight proteinuria is frequently observed in patients at these stages (Pontuch et al 1992;Hong et al 2003). Therefore, the altered regulation of megalin expression and its functions must be primarily responsible for the early development of proteinuria/albuminuria in diabetic patients.…”

Section: Megalinmentioning

confidence: 99%

Hormonal Actions and Interactions in Proximal Tubule Cells Associated with the Development of Chronic Kidney Disease

Saito¹,

Hosojima²,

Sato³

2011

Basic and Clinical Endocrinology Up-to-Date

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Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Cited by 112 publications

References 53 publications

Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats

Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

Hormonal Actions and Interactions in Proximal Tubule Cells Associated with the Development of Chronic Kidney Disease

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