Regulation and consequences of differential gene expression in diabetic kidney disease

Murphy, Madeline; Crean, John; Brazil, Derek P.; Sadlier, Denise; Martin, Finian; Godson, Catherine

doi:10.1042/bst0360941

Cited by 32 publications

(20 citation statements)

References 25 publications

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“…TGF-β1, a multifunctional cytokine that induces the differentiation of fibroblasts to myofibroblasts, is implicated as a key inducer of fibrotic diseases, including diabetic nephropathy and hypertensive nephropathy [16,17]. TGF-β1 induces fibrogenesis through smooth muscle cell proliferation, stimulation of extracellular matrix proteins, and inhibition of matrix degradation [18,19].…”

Section: Discussionmentioning

confidence: 99%

Renoprotective Effects of Sildenafil in DOCA-Salt Hypertensive Rats

Bae¹,

Kim

Joo

et al. 2012

Kidney Blood Press Res

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Background/Aims: Sildenafil, the first selective phosphodiesterase-5 (PDE5) inhibitor to be widely used for treating erectile dysfunction, has been investigated with regard to its cardioand renoprotective effects in animal models. This study further investigated the renoprotective effects of sildenafil and their molecular mechanisms in deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. Methods: DOCA strips (200 mg/kg) were implanted in rats 1 week after unilateral nephrectomy. These rats were fed on a control diet, with or without sildenafil (50 mg·kg^–1day^–1), for 2 weeks. Systolic blood pressure (SBP) was measured by the tail cuff method, and the urinary albumin-to-creatinine ratio (ACR) was calculated. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson’s trichrome stain. Renal expression of ED-1, transforming growth factor-β1 (TGF-β1), Bax, and Bcl-2 were determined by semiquantitative immunoblotting, polymerase chain reaction (PCR), and immunohistochemistry. TUNEL staining was used for detecting apoptotic cells. Results: The increased SBP in DSH rats was not attenuated by sildenafil treatment. The decreased creatinine clearance and increased ACR in DSH rats, compared with control animals, were attenuated by sildenafil treatment. Further, sildenafil treatment attenuated glomerulosclerosis and tubulointerstitial fibrosis in DSH rats and counteracted the increased expression of ED-1, TGF-β1, and Bax and the decreased expression of Bcl-2 in the kidneys of these rats. The increase in the number of apoptotic cells in DSH rats was attenuated by sildenafil treatment. Conclusion: Sildenafil effectively prevented the progression of renal injury in DSH rats via its anti-inflammatory, antifibrotic, and antiapoptotic effects.

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Section: Discussionmentioning

confidence: 99%

Renoprotective Effects of Sildenafil in DOCA-Salt Hypertensive Rats

Bae¹,

Kim

Joo

et al. 2012

Kidney Blood Press Res

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“…Many of these same morphologic transitions reflect, in large part, changes in transcriptional outputs in response to increasing levels of TGF-β1 in the renal parenchyma and, therefore, are superimposed on the time course of tubulointersitial fibrosis. Several comprehensive databases, derived from microarray profiling, provide critical insights into the spectrum of differential gene expression patterns in renal disease (Murphy et al 2008; Ju et al 2009; Matsuo et al 2005; Silverstein et al 2003; Higgins et al 2003; Eikmans et al 2003; Sadlier et al 2004; Seseke et al 2004) and in response to TGF-β1 (for reviews, see Freytag et al 2009, 2010). PAI-1, in particular, is a prominent member of, if not the most highly upregulated gene in, the TGF-β1-induced gene set (Freytag et al 2009; Zavadil et al 2001; Akiyoshi et al 2001) and is causatively involved in the development of the EMT phenotype (Freytag et al 2010).…”

Section: Tgf-β Target Genes: Causative Roles In Pathogenesismentioning

confidence: 99%

TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis

et al. 2011

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Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone. Diabetes, hypertension, ischemia, acute injury, and urological obstruction contribute to renal fibrosis, a common pathological hallmark of chronic kidney disease. Regardless of etiology, elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin, glucose, and oxidative stress. Unilateral ureteral obstruction (UUO) is a useful and accessible model to identify mechanisms underlying the progression of renal fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a major effector and downstream target of TGF-β1 in the progression of several clinically important fibrotic disorders, is highly up-regulated in UUO and causatively linked to disease severity. SMAD and non-SMAD pathways (pp60c-src, epidermal growth factor receptor [EGFR], mitogen-activated protein kinase, p53) are required for PAI-1 induction by TGF-β1. SMAD2/3, pp60c-src, EGFR, and p53 activation are each increased in the obstructed kidney. This review summarizes the molecular basis and translational significance of TGF-β1-stimulated PAI-1 expression in the progression of kidney disease induced by ureteral obstruction. Mechanisms discussed here appear to be operative in other renal fibrotic disorders and are relevant to the global issue of tissue fibrosis, regardless of organ site.

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“…Diabetic nephropathy (DN) is one of the leading microvascular complication in patients with diabetes, and is the most prevalent cause of chronic renal failure [1, 2]. Fundamentally, chronic hyperglycemia is regarded as the main metabolic denominator that seems to be responsible for the development of DN.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy

Hu¹,

Sun²,

Xiao³

et al. 2015

CMC

170

113

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Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel–Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch though Notch1/Jagged1 signaling, Wnt by Wnt/β-catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2-dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy.

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Regulation and consequences of differential gene expression in diabetic kidney disease

Cited by 32 publications

References 25 publications

Renoprotective Effects of Sildenafil in DOCA-Salt Hypertensive Rats

Renoprotective Effects of Sildenafil in DOCA-Salt Hypertensive Rats

TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis

Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy

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