From Fibrosis to Sclerosis

Qian, Ying; Feldman, Eva L.; Pennathur, Subramanian; Kretzler, Matthias; Brosius, Frank C.

doi:10.2337/db08-0061

Cited by 281 publications

(194 citation statements)

References 77 publications

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“…This may also play a role in diabetic glomerulosclerosis because glomerular mesangial cells share many structural and functional characteristics with vascular smooth muscle cells [26] and significantly contribute to the remodelling process of the glomerular matrix [23]. Histone H3 phosphorylation of Ser-10 is another marker of chromatin relaxation and gene expression [3,22], but its role in diabetes has not yet been explored. Our data generate first evidence that three distinct H3 modifications, all known to promote nucleosome unwinding and gene expression, are consistently associated with glomerular cell proliferation during the progression to advanced diabetic glomerulosclerosis in db/db mice.…”

Section: Discussionmentioning

confidence: 99%

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Sayyed

Gaikwad

Lichtnekert

et al. 2010

Nephrology Dialysis Transplantation

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Background. Distinct histone modifications regulate gene expression in certain diseases but little is known about histone epigenetics in diabetic nephropathy. The current study examined the role of histone epigenetics in development and progression of nephropathy in db/db mice. Methods. We studied kidney damage in 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Histone H3K9 and H3K23 acetylation, H3K4 and H3K9 dimethylation and H3 phosphorylation at serine 10 was explored by western blotting of renal histone extracts. Results. Uninephrectomy in C57BL/6 mice or onset of diabetes in type 2 diabetes reduced renal H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10. In contrast, H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 were significantly increased in uninephrectomized db/db mice. The disease pattern of these mice is characterized by an increased glomerular cell proliferation, severe glomerulosclerosis, albuminuria and glomerular filtration rate reduction. Treating uninephrectomized db/db mice with a Mcp-1/Ccl2 antagonist prevented the histopathological damage and the aforementioned histone modification abnormalities of advanced diabetic glomerulosclerosis. Conclusion. We conclude that advanced diabetic nephropathy is associated with increased renal H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 that enhance chromatin unfolding and gene expression.

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Section: Discussionmentioning

confidence: 99%

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Sayyed

Gaikwad

Lichtnekert

et al. 2010

Nephrology Dialysis Transplantation

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“…[1][2][3][4][5][6] Development and progression of DN involve a complex interplay among metabolic, hemodynamic, growth, and inflammatory factors. 1,3,[7][8][9][10][11][12][13] The progressive decline in renal function during DN is a result of a multitude of pathologic changes in the kidneys, including glomerular and tubular hypertrophy, macrophage infiltration, extracellular matrix (ECM) accumulation in multiple renal cells, mesangial expansion, endothelial dysfunction, and podocyte injury. 1,3,[7][8][9][10][11][12][14][15][16] These pathologic changes clinically manifest as proteinuria and a steady deterioration in GFR.…”

mentioning

confidence: 99%

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Bhatt

Lanting

Jia

et al. 2015

JASN

158

130

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Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a 2/2 mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a 2/2 than in the kidneys of wild-type mice. Notably, miR146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1b and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a 2/2 mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a 2/2 mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN. 27: 227727: -228827: , 201627: . doi: 10.1681 Diabetic nephropathy (DN) is the leading cause of CKD and ESRD. 1-6 Development and progression of DN involve a complex interplay among metabolic, hemodynamic, growth, and inflammatory factors. 1,3,[7][8][9][10][11][12][13] The progressive decline in renal function during DN is a result of a multitude of pathologic changes in the kidneys, including glomerular and tubular hypertrophy, macrophage infiltration, extracellular matrix (ECM) accumulation in multiple renal cells, mesangial expansion, endothelial dysfunction, and podocyte injury. 1,3,[7][8][9][10][11][12][14][15][16] These pathologic changes clinically manifest as proteinuria and a steady deterioration in GFR. 3,4,16 Identification of molecular pathways that contribute to the pathophysiology of DN is imperative for the development of new therapeutic strategies. J Am Soc NephrolConversely, identification of factors that exert adaptive and protective roles in the early stages of DN can be exploited to prevent progression to ESRD.

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“…In fact, extracellular HSPA1A may act as a danger signal and trigger immunological responses (Mansilla et al 2012). Interstitial fibrosis and glomerulosclerosis are two main pathological features of diabetic nephropathy, and inflammation plays a key role in the development of both (Qian et al 2008). Inflammation may initially exert a protective response against hyperglycemia, but it turns into a detrimental condition if chronically persisted (Lawrence and Gilroy 2007).Unresolved renal inflammation promotes progressive fibrosis of glomerulus and tubulointerstitial structures (Meng et al 2014).…”

Section: Discussionmentioning

confidence: 99%

The lost correlation between heat shock protein 70 (HSPA1A) and plasminogen activator inhibitor-1 in patients with type 2 diabetes and albuminuria

Nargesi

Shalchi

Nargesi

et al. 2016

Cell Stress and Chaperones

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We aimed to study the relation between plasma levels of stress-induced heat shock protein 70 (HSPA1A) with plasminogen activator inhibitor-1 (PAI-1) and highdensity lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1), and HDL-C/Apo-A1 ratio. In a matched case-control study on patients with diabetes (40 patients with albuminuria and 40 without albuminuria matched for age, sex, and body mass index), we observed that plasma levels of HSPA1A and PAI-1 are increased in patients with albuminuria (0.55±0.02 vs. 0.77±0.04 ng/ml, p value <0.001 for HSPA1A; 25.9±2 vs. 31.8±2.4 ng/ml, p value <0.05 for PAI-1). There was a significant correlation between HSPA1A and PAI-1 in diabetic patients without albuminuria (r=0.28; p value=0.04), but not in those with albuminuria (r=0.07; p value=0.63). No association was found between HSPA1A and HDL-C, between HSPA1A and Apo-A1, or between HSPA1A and HDL-C/Apo-A1 ratio. We concluded that there is a direct correlation between plasma HSPA1A and PAI-1 levels in patients with diabetes, which is lost when they develop albuminuria.

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From Fibrosis to Sclerosis

Cited by 281 publications

References 77 publications

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

The lost correlation between heat shock protein 70 (HSPA1A) and plasminogen activator inhibitor-1 in patients with type 2 diabetes and albuminuria

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