Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy

Yabuki, Akira; Taniguchi, Kazuyuki; Yamato, Osamu

doi:10.1538/expanim.59.479

Cited by 6 publications

(5 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glomerular effects of COX-2 are supported by the fact that macula densa COX-2 expression peaks at a time earlier than glomerular COX-2[58]. Hyperglycemia augments COX-2 mediated-hyperfiltration but lessens the ability of COX-2 to increase GFR in hyperfiltering patients [56] and might signify increased compromise of the glomerular barrier (in addition to vasodilation) mediated by COX-2.…”

Section: Diabetic Nephropathy: More Than Cox-2 Dysregulation Of Hemodmentioning

confidence: 99%

See 1 more Smart Citation

The complex interplay between cyclooxygenase-2 and angiotensin II in regulating kidney function

Green

González

Mitchell

et al. 2012

Current Opinion in Nephrology &Amp; Hypertension

View full text Add to dashboard Cite

Purpose of Review Cyclooxygenase-2 (COX-2) plays a critical role in modulating deleterious actions of angiotensin II (Ang II) where there is an inappropriate activation of the renin-angiotensin system (RAS). This review discusses recent developments regarding the complex interactions by which COX-2 modulates the impact of an activated RAS on kidney function and blood pressure. Recent Findings Normal rats with increased COX-2 activity but with different intrarenal Ang II activity due to sodium restriction or chronic treatment with angiotensin converting enzyme (ACE) inhibitors showed similar responses to COX-2 selective inhibition (nimesulide) indicating independence from the intrarenal Ang II activity. COX-2 dependent maintenance of medullary blood flow was consistent and not dependent on dietary salt or ACE inhibition. In contrast, COX-2 influences on sodium excretion were contingent on the prevailing RAS activity. In chronic hypertensive models, COX-2 inhibition elicited similar reductions in kidney function but COX-2 metabolites contribute to rather than ameliorate the hypertension. Summary The maintenance of renal hemodynamics reflects direct and opposing effects of Ang II and COX-2 metabolites. The antagonism in water and electrolyte reabsorption is dependent on the prevailing intrarenal Ang II activity. The recent functional experiments demonstrate a beneficial modulation of Ang II by COX-2 except in the presence of inflammation promoted by hypertension, hyperglycemia and oxidative stress.

show abstract

Section: Diabetic Nephropathy: More Than Cox-2 Dysregulation Of Hemodmentioning

confidence: 99%

“…In female diabetic patients, Ang II-mediated reductions in GFR were abolished by COX-2 inhibition [60]. Glomerular COX-2 expression is correlated with glomerular sclerosis to a higher degree than renin-positivity[58]. Studies also show association between RAS activity and COX-2 expression.…”

Section: Diabetic Nephropathy: More Than Cox-2 Dysregulation Of Hemodmentioning

confidence: 99%

The complex interplay between cyclooxygenase-2 and angiotensin II in regulating kidney function

Green

González

Mitchell

et al. 2012

Current Opinion in Nephrology &Amp; Hypertension

View full text Add to dashboard Cite

show abstract

“…17 Furthermore, in most mouse strains, diabetes induces relatively minor glomerular pathology. 18 In this regard, our preliminary studies indicated that in wild-type B6/D2 mice, the strain used to generate the transgenic animals, low-dose streptozotocin-induced (STZ-induced) diabetes did not induce significant diabetic nephropathy, and renal COX-2-positive cells were rare under both basal and diabetic conditions.…”

Section: Podocyte Cox-2 Expression In Diabetesmentioning

confidence: 99%

Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression

Cheng¹,

Fan²,

Moeckel³

et al. 2011

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Diabetic nephropathy (DN) increases podocyte cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition reduces proteinuria and glomerular injury in animal models of diabetes. To investigate the role of podocyte COX-2 in development of diabetic nephropathy, we employed a streptozotocin model of diabetic mellitus in wild-type and transgenic mice expressing COX-2 selectively in podocytes. Progressive albuminuria developed only in diabetic COX-2 transgenic mice despite hyperglycemia, BP, and GFR being similar to those in wild-type mice. Transgenic mice also manifested significant foot-process effacement, moderate mesangial expansion, and segmental thickening of the glomerular basement membrane. In cultured podocytes overexpressing COX-2, high glucose induced cell injury and increased both expression of the pro(renin) receptor and activation of the renin-angiotensin system. Downregulation of the (pro)renin receptor attenuated the injury induced by high glucose. In vivo, podocyte pro(renin) receptor expression increased in diabetic COX-2-transgenic mice, and treatment with a COX-2 inhibitor abrogated the upregulation of (pro)renin receptor and reduced albuminuria, footprocess effacement, and mesangial matrix expansion. In summary, these results demonstrate that increased expression of podocyte COX-2 predisposes to diabetic glomerular injury and that the (pro)-renin receptor may be one mediator for this increased susceptibility to injury. Hyperglycemia-mediated metabolic abnormalities, hemodynamic abnormalities, and oxidative stress have all been implicated in the pathogenesis of diabetic nephropathy. 1 Diabetes can affect numerous cell types in the kidney, including glomerular podocytes, mesangial and endothelial cells, tubular epithelia, interstitial fibroblasts, and vascular endothelia. 2 Altered podocyte function occurs early in the development of diabetic nephropathy and can affect cell-cell interactions, attachment to the glomerular basement membrane, and apoptosis. [2][3][4][5][6][7][8][9][10] In humans, COX-2 expression is readily detectable in glomerular podocytes of adults, 11,12 and expression levels have been reported to increase during acute renal allograft rejection. 13,14 Occasional COX-2-positive podocytes are also detectable in adult rats, 15,16 and we have previously reported that in rat models of diabetes there is increased COX-2 expression in podocytes, and also in mesangial cells and macula densa cells, and have shown that COX-2 inhibition can attenuate proteinuria and retard diabetic nephropathy progression. 15 In this study, we investigated the role of increased COX-2 in diabetes-induced podocyte injury. Our results indicate that increased podocyte expression of COX-2 increases susceptibility

show abstract

“…This mouse serves as a model of obese insulin‐resistant T2DM showing hyperglycemia, hypertriglyceridemia and hyperinsulinemia. This experimental model has been used to investigate diabetic nephropathy (Yabuki et al ., ) and has been recently applied in pharmacological studies for the improvement of cognitive decline by angiotensin II type 1 receptor blocker in the brain (Min et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Increased methylmercury toxicity related to obesity in diabetic KK‐Ay mice

Yamamoto

Yanagisawa

Motomura

et al. 2013

J of Applied Toxicology

View full text Add to dashboard Cite

We examined the toxic effects of methylmercury (MeHg) in KK-Ay type 2 diabetic mice to clarify how metabolic changes associated with type 2 diabetes mellitus affect MeHg toxicity. MeHg (5 mg Hg kg (-1) day(-1) p.o.) was given to 4-week-old male KK-Ay and C57BL/6J (BL/6) mice three times per week for 6 weeks. Average body weights (BW) of vehicle-treated BL/6 and KK-Ay mice were 16.3 and 16.4 g respectively on the first day, and 24.8 and 42.3 g respectively on the last day of the experiment. MeHg-treated KK-Ay mice began to lose weight about 5 weeks after MeHg administration. Six of seven MeHg-treated KK-Ay mice showed hind-limb clasping in the final stage of the experiment. The mean blood mercury level of MeHg-treated KK-Ay mice reached a maximum of 9.8 µg ml(-1) , whereas that of the MeHg-treated BL/6 mice was 2.8 µg ml(-1) after 10 days of treatment. The average total mercury concentrations in the cerebrum and epididymal fat pad were 7.4 and 0.57 µg g(-1) , respectively, for BL/6 mice and 27 and 1.6 µg g(-1) , respectively, for KK-Ay mice. In MeHg-treated KK-Ay mice with neurological symptoms, CD204-positive macrophages were observed in the brain, kidney and spleen, indicating CD204 could be a marker for injured tissues. BW loss and significant pathological changes were not observed in other groups of mice. These results indicate that body fat gain in type 2 diabetes mellitus and low mercury accumulation in adipose tissue increased MeHg concentrations in organs and enhanced toxicity in KK-Ay mice at the same dose of MeHg per BW.

show abstract

Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy

Cited by 6 publications

References 30 publications

The complex interplay between cyclooxygenase-2 and angiotensin II in regulating kidney function

The complex interplay between cyclooxygenase-2 and angiotensin II in regulating kidney function

Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression

Increased methylmercury toxicity related to obesity in diabetic KK‐Ay mice

Contact Info

Product

Resources

About