Proinsulin C‐peptide abrogates type‐1 diabetes‐induced increase of renal endothelial nitric oxide synthase in rats

Kamikawa, Akihiro; Ishii, Tatsuya; Shimada, Kohei; Makondo, Kennedy; Inanami, Osamu; Sakane, Naoki; Yoshida, Toshihide; Saito, Masayuki; Kimura, Kazuhiro

doi:10.1002/dmrr.810

Cited by 32 publications

(33 citation statements)

References 35 publications

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“…We report increased fractional urinary Na ϩ excretion and decreased transport-related cellular QO 2 after C-peptide administration, which demonstrates an inhibitory effect of C-peptide on Na ϩ -K ϩ -ATPase in the kidney. Indeed, the effects of C-peptide on endothelial NO synthase under normoglycemic conditions are different from those under hyperglycemic conditions (21,26).…”

Section: Discussionmentioning

confidence: 98%

Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption

Nordquist

Brown

Fasching

et al. 2009

American Journal of Physiology-Renal Physiology

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C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.

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Section: Discussionmentioning

confidence: 98%

Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption

Nordquist

Brown

Fasching

et al. 2009

American Journal of Physiology-Renal Physiology

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“…Pharmacological intervention aimed at lowering glomerular capillary pressure would represent an ideal therapeutic site to slow the progression of renal injury in diabetes. Although previously reported in various tissues to stimulate NO, recent studies have shown that C-peptide counteracts diabetes-induced eNOS levels within the kidney [51]. Ultimately this will reduce inappropriate vasodilation of the arteriole, an effect which fails to diminish renal blood flow [52] and is thus thought matched by dilation of the efferent arteriole.…”

Section: Molecular Mechanisms Of C-peptide Actionmentioning

confidence: 99%

C-Peptide as a Therapeutic Tool in Diabetic Nephropathy

2010

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Background/Aims: Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes. Methods: To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN. Results: Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-ĸB and peroxisome proliferator-activated receptor-γ. Conclusion: Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.

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“…NO plays a diverse role in protecting the host from bacterial and fungal pathogens, either through direct or indirect effects, or through involvement of oxidative processes (Fang 1997). Even though C-peptide has been reported with regard to NOS (Kitamura et al 2003;Kamikawa et al 2008), the exact mechanisms are still unclear.…”

Section: Introductionmentioning

confidence: 99%

C-peptide stimulates nitrites generation via the calcium-JAK2/STAT1 pathway in murine macrophage Raw264.7 cells

Lee

Kim

et al. 2010

Life Sciences

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Proinsulin C‐peptide abrogates type‐1 diabetes‐induced increase of renal endothelial nitric oxide synthase in rats

Abstract: The results indicate that C-peptide suppresses diabetes-induced abnormal renal eNOS expression, by which C-peptide may exert beneficial effects on diabetic nephropathy.

Cited by 32 publications

References 35 publications

Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption

Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption

C-Peptide as a Therapeutic Tool in Diabetic Nephropathy

C-peptide stimulates nitrites generation via the calcium-JAK2/STAT1 pathway in murine macrophage Raw264.7 cells

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