Long-term expression of glomerular genes in diabetic nephropathy

Chittka, Dominik; Banas, Bernhard; Lennartz, L.; Putz, Franz Josef; Eidenschink, Kathrin; Beck, Sebastian; Stempfl, Thomas; Moehle, Christoph; Reichelt-Wurm, Simone; Banas, Miriam C.

doi:10.1093/ndt/gfx359

Cited by 14 publications

(14 citation statements)

References 40 publications

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“…Among these mechanisms, fatty acid and cellular lipid metabolic dysregulation are of particular interest because lipid abnormalities are increasingly recognized by our group and others as independent risk factors for DKD development. [58][59][60] Importantly, these results are also consistent with recent findings in multiple type 2 diabetic mouse models such as the KK-Ay mouse 61 and the BTBR ob/ob leptin-deficient mouse, 62 further reinforcing our data. Since our findings in this report show association and not causality, direct effects of these increased and decreased gene expression changes will need to be verified experimentally.…”

Section: Discussionsupporting

confidence: 92%

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects

et al. 2021

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Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome-wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS−/− mice receiving renin-angiotensin-aldosterone system (RAS)-blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data analysis method, SOM, or self-organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatic analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro-inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAS exacerbated expression of genes related to inflammation and 2 of 17 | EID Et al.

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Section: Discussionsupporting

confidence: 92%

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects

et al. 2021

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“…Since we used the renal cortex instead of morphologically dissected glomeruli, this makes direct comparisons difficult. Nonetheless, a number of the reported differentially expressed genes were also found in our data set, e.g., Hdc, Hyal, Hmgcs2, C3, albeit that the total number of DEGs we found was significantly lower than in the study of Chittka et al [31]. Although this is partly due to the use of different arrays (Mouse Whole Transcriptome 1.0 ST array vs.…”

Section: Discussioncontrasting

confidence: 79%

“…Even though renal and serum parameters, as well as some of the histological features in renal tissue, were worse in hCN1 TG mice, the number of DEGs was limited to a subset of 26 genes with a FC-threshold of > 1.5. We cannot, however, exclude that the differences in gene expression profile between diabetic TG and nonTG mice would have been larger if glomeruli were analyzed selectively as previously reported by Chittka et al [31]. Amongst the 26 DEG in diabetic hCN1 TG mice, many have been reported to be pivotal in the pathogenesis of DKD.…”

Section: Discussionmentioning

confidence: 81%

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Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice

et al. 2020

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Objective To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). Methods hCN1 transgenic (TG) mice were generated in a BTBR Ob/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBR Ob/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBR Ob/Ob mice. Results hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBR Ob/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumincreatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBR Ob/Wt , BTBR Ob/Ob, and hCN1 BTBR Ob/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator-activated receptor-alpha have been reported to play essential roles in DKD. Conclusions Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. Jiedong Qiu, Thomas Albrecht and Shiqi Zhang contributed equally to this work. An abstract of this work has been awarded a poster prize on the congress of the German Diabetes Association (DDG) 2018 and on the International Congress on Carnosine and Anserine (ICCA) 2017 and has been presented on the congress of the European Association for the Study of Diabetes (EASD) 2018.

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“…Further studies have shown dysregulation of Sema5A and Sema5E in diabetic nephropathy [105]. A large transcriptional dataset on human diabetic glomeruli shows Sema5A and Sema3G are among the top 100 dysregulated transcripts and "semaphorin signaling in neurons" as one of the enriched pathways [128].…”

Section: Semaphorins In Diabetic Nephropathymentioning

confidence: 99%

The Role of Semaphorins in Metabolic Disorders

Zhu

2020

IJMS

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Semaphorins are a family originally identified as axonal guidance molecules. They are also involved in tumor growth, angiogenesis, immune regulation, as well as other biological and pathological processes. Recent studies have shown that semaphorins play a role in metabolic diseases including obesity, adipose inflammation, and diabetic complications, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic wound healing, and diabetic osteoporosis. Evidence provides mechanistic insights regarding the role of semaphorins in metabolic diseases by regulating adipogenesis, hypothalamic melanocortin circuit, immune responses, and angiogenesis. In this review, we summarize recent progress regarding the role of semaphorins in obesity, adipose inflammation, and diabetic complications.

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Long-term expression of glomerular genes in diabetic nephropathy

Abstract: The gene profile of BTBR ob/ob type 2 diabetic mice we conducted in this study can help to identify new key players in molecular pathogenesis of diabetic kidney injury.

Cited by 14 publications

References 40 publications

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice

The Role of Semaphorins in Metabolic Disorders

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