Chronic Inhibition of Nitric Oxide Production Aggravates Diabetic Nephropathy in Otsuka Long-Evans Tokushima Fatty Rats

Kamijo, Hiroshi; Higuchi, Makoto; Hora, Kazuhiko

doi:10.1159/000093276

Cited by 24 publications

(18 citation statements)

References 42 publications

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“…This idea subsequently received experimental support in type 2 diabetes complicated by nephropathy (27). The overarching microvascular damage hypothesis is consistent with our current findings of loss of renal vascular barrier function, and those of others regarding defective renal nitric oxide synthesis (14), which presumably amplifies renal vasculopathy and resulting nephropathy (18).…”

Section: Discussionsupporting

confidence: 91%

Microcirculation: nexus of comorbidities in diabetes

Temm¹,

Dominguez²

2007

American Journal of Physiology-Renal Physiology

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Generalized capillary dysfunction is a morbid element in the metabolic syndrome, and it is likely involved in its complications. We tested the hypothesis that vast amounts of serum albumin previously observed in kidneys of rats with the metabolic syndrome were caused, in part, by leakage from renal peritubular capillaries. We report herein large scale leaks of plasma fluid in peritubular capillaries of rats with the metabolic syndrome. This finding was directly demonstrated in vivo, and the presence of leftover albumin residue confirmed the leak in postmortem kidney specimens. Moreover, renal interstitial fibrosis and tubular atrophy were found in a distribution similar to the leaked renal albumin in obese rats. We suggest that there is an important link between peritubular capillary damage and interstitial fibrosis, represented as tubulointerstitial disease in the metabolic syndrome. We propose that maintenance of the peritubular microcirculation may improve renal outcomes in diabetes and the metabolic syndrome. diabetic nephropathies; capillary permeability GENERALIZED CAPILLARY DYSFUNCTION is an important pathogenic mechanism of nephropathy and other complications of uncontrolled diabetes (6, 27). One logical inference from this notion is that glomerular and peritubular capillaries are similarly damaged in diabetic nephropathy. However, the focal point of research on diabetic nephropathy has been the glomerulus (15,38,39), and the prospect of significant injury to postglomerular capillaries has received less attention. Investigators have proposed that postglomerular microvessels are damaged in diabetic nephropathy (6), and some experimental support has been advanced (2, 16), prompting the suggestion that damage to peritubular capillaries alters tubular function (16). However, peritubular vasculopathy has the potential of being far more detrimental, as compromised delivery of oxygen and nutrients is potentially lethal to renal tubules (11,19). In fact, chronic peritubular capillary insufficiency might be a major contributor to tubular death and to interstitial fibrosis (1), both common features of progressive nephropathy in the metabolic syndrome (7,8).Capillary leaks of hearts, kidneys, and retinas have been described with various degrees of precision in diabetic rats (21,31,37), affirming the view that capillary damage is at least a component, if not an important source, of diabetes complications. We recently found large quantities of rat serum albumin in kidneys of male rats with nephropathy of the metabolic syndrome (7) and hypothesized a severe leakage of blood plasma into the renal interstitium, most likely from postglomerular capillaries. Hence, we searched for postglomerular capillary leakage of macromolecules in male rats with nephropathy of the metabolic syndrome. We studied F 1 generation hybrid male rats, the product of Zucker diabetic fatty (ZDF) and spontaneous hypertensive heart failure rats (ZS rats) which prominently depict all common features of the metabolic syndrome (7). We used two-photon ...

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Section: Discussionsupporting

confidence: 91%

Microcirculation: nexus of comorbidities in diabetes

Temm¹,

Dominguez²

2007

American Journal of Physiology-Renal Physiology

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“…82 In addition, full NOS3 deficiency sensitizes mice to type I 31 or type II DN. 83,84 Furthermore, the ¡786C NOS3 gene variant is associated with a high urine albumin-to-creatinine ratio and a high risk of albuminuria in European American families. 85 The low expression of NOS3 in mice, comparable to that associated with human NOS3 variants, promotes diabetic nephropathy independent of its effects on blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

et al. 2015

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filtration barrier; MAP1LC3A/B/LC3A/B), microtubule-associated protein 1 light chain 3 a/b; MTOR, mechanistic target of rapamycin; Nphs2, nephrosis 2, podocin; SQSTM1, sequestosome 1; STZ, streptozotocin; TEM, transmission electron microscopy; TUBA, tubulin; a, WT1, Wilms tumor 1.The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelialspecific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.

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“…As NO may increase both blood flow and vascular permeability, it has been suggested as an important mediator responsible for the vascular changes that have been described in early diabetic nephropathy [28]. However, in several studies [29,30,31,32], inhibition of NO action and genetic variation of NO synthetase exacerbate, not attenuate, diabetic nephropathy. These findings suggest that increased production of NO in early diabetic nephropathy is compensative for blood pressure elevation or vascular endothelial damage.…”

Section: Discussionmentioning

confidence: 99%