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Activation of the renal renin-angiotensin system in diabetes--new concepts

2008; Oxford University Press; Volume: 23; Issue: 10 Linguagem: Inglês

10.1093/ndt/gfn377

1460-2385

János Peti‐Peterdi, Jung Julie Kang, Ildikó Toma,

Hormonal Regulation and Hypertension

The incidence of diabetes mellitus, obesity and the metabolic syndrome is rapidly rising to epidemic levels worldwide. Hyperglycemia, the metabolic hallmark of the pathology, is a significant causative factor for the complications of diabetes mellitus which result in significant morbidity and mortality for millions. Hyperglycemia is clearly associated with microvascular complications in many organs including the kidney, and diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in developed countries [1,2]. In addition, diabetes may lead to other vascular complications, including systemic hypertension [1,2]. Recent advances on the cellular and kidney-specific effects of hyperglycemia place activation of the local, intrarenal renin–angiotensin system (RAS) as a strong candidate for the core abnormality that leads to renal tissue injury [1–3]. The nature of RAS activation in diabetes is, however, controversial [3]. It has been difficult to isolate the acute and direct actions of hyperglycemia per se from the many other systemic factors and intra-renal, macula densa-mediated feedback mechanisms that can indirectly activate the intrarenal RAS. Therefore, the primary cause and exact mechanism of RAS activation in early diabetes have been unknown. The prevailing paradigm, the ‘tubular hypothesis of glomerular filtration’ [4], argues that the two hallmarks of early changes, glomerular hyperfiltration and renin activation, originate from the primary effects of glucose on proximal tubule salt reabsorption that secondarily activate macula densa-mediated feedback mechanisms. However, the development of diabetes-induced glomerular hyperfiltration was intact, or even augmented, in mice that lacked tubuloglomerular feedback (TGF), demonstrating that the TGF mechanism could not be the major cause of the development of hyperfiltration [5,6].