Genetic basis of diabetic kidney disease and other diabetic complications

Sandholm, Niina; Groop, Per‐Henrik

doi:10.1016/j.gde.2018.01.002

Cited by 32 publications

(16 citation statements)

References 51 publications

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“…It is now clear that there is large variability in susceptibility of widely used inbred mouse strains to albuminuria and glomerulosclerosis in DN. Moreover, susceptibility loci for DN have been identified in humans . It is possible that the genetic changes that make Dahl SS rats a good model for studies of hypertension result in enhanced TRPC6 signaling somewhere within the animal (possibly but not necessarily within glomeruli).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, susceptibility loci for DN have been identified in humans. 45 It is possible that the genetic changes that make Dahl SS rats a good model for studies of hypertension 38 result in enhanced TRPC6 signaling somewhere within the animal (possibly but not necessarily within glomeruli). In this regard, Dahl SS rats typically exhibit slightly increased urine albumin excretion, even on low-salt diets.…”

Section: Discussionmentioning

confidence: 99%

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TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

2019

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Canonical transient receptor potential‐6 (TRPC6) channels have been implicated in the progression of several forms of kidney disease (1). While there is strong evidence that glomerular TRPC6 channels are dysregulated in diabetic nephropathy (DN), there is no consensus as to whether deletion or inactivation of TRPC6 is protective in animal models of DN. A previous study in Dahl salt‐sensitive rats suggests that TRPC6 knockout has a modest protective effect in streptozotocin (STZ)‐induced DN (2). In the present study, we examined whether inactivation of TRPC6 channels by CRISPR/Cas9 editing (Trpc6del/del rats) affects progression of STZ‐induced DN in Sprague‐Dawley rats. Wild‐type littermates (Trpc6wt/wt rats) were used as controls. We observed that a single injection of STZ resulted in severe hyperglycemia that was sustained over a 10‐week period, accompanied by a marked reduction in circulating C‐peptide, dyslipidemia, and failure to gain weight compared to vehicle‐treated animals. Those effects were equally severe in Trpc6wt/wt and Trpc6del/del rats. STZ treatment resulted in increased urine albumin excretion at 4, 8, and 10 weeks after injection, and this effect was equally severe in Trpc6wt/wt and Trpc6del/del rats. TRPC6 inactivation had no effect on blood urea nitrogen (BUN), plasma creatinine concentration, urine nephrin excretion, or kidney weight:body weight ratio measured 10 weeks after STZ injection. STZ treatment evoked modest and equivalent mesangial expansion in Trpc6wt/wt and Trpc6del/del rats. In summary, we observed no protective effect of TRPC6 inactivation on STZ‐induced DN in rats on the Sprague‐Dawley background.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

2019

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“…SNP могут влиять на предрасположенность к различным заболеваниям, скорость и тяжесть развития осложнений [6,7], а также чувствительность к лекарственным препаратам [8,9], что было показано во многих работах, в том числе изучающих СД2, по данным которых его наследуемость в некоторых семьях достигает 80% [10]. На современном этапе в арсенале исследователей имеются 4 основных подхода-стратегии к изучению роли SNP в патогенезе СД2, а именно:…”

Section: актуальностьunclassified

Genetic Variants Associated with the Development of Type 2 Diabetes: Approaches to Their Identification

et al. 2019

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In the development of type 2 diabetes (T2D), an important role is played by a combination of environmental factors (hypodynamia, hypernutrition, etc.) and genetic variants that predispose the development of the disease. The contribution of inherited traits to the development of T2D can reach 80%, which is confirmed by the results of a number of published studies. At the same time, the multifactorial and polygenetic nature of T2D makes it difficult to establish direct cause-effect relations between individual genetic variants and specific metabolic changes. This explains a large number of studies and a long ongoing search for the most convenient and effective strategy for assessing the role of single nucleotide polymorphisms (SNP), the main type of genetic variation in the human genome. Involvement of specialists from various fields and the emergence of many methods for processing and interpreting data have led to the parallel development of scientific approaches. In this review of the main approaches (except mathematical ones) their characteristics will be described and the results obtained with their help will be evaluated, with special focus on new features of modern methods of genome editing, in particular the CRISPR/Cas9 system, and the future prospects in this area.

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“…Genome-wide association studies (GWAS) have had limited success in identifying genetic factors that predict kidney disease progression, despite major financial investment and the study of more than 10,000 patients. This lack of success is likely due to inter-individual heterogeneity in kidney disease progression, even in disease subtypes characterized by similar aetiology 1 . The progression of diabetic kidney disease, for example, is highly variable and the rate of decline in kidney function only partly correlates with urine albumin to creatinine ratio (ACR), blood pressure and glycaemic control 2,3 .…”

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confidence: 99%