Lessons From the KK-Ay Mouse, a Spontaneous Animal Model for the Treatment of Human Type 2 Diabetic Nephropathy

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Abstract

Diabetic nephropathy is a major cause of end-stage kidney disease (ESKD) in patients with type 1 and type 2 diabetes throughout the world. In human glomeruli, expansion of diffuse mesangial matrices, exudative lesions and/or segmental nodular sclerosis are pathological features of diabetic nephropathy. There have been many reports on the pathogenesis and treatment of type 2 diabetes using various animal models.

It appears that KK-Ay mice, especially in terms of their immunohistological findings, are a suitable animal model for human type 2 diabetic nephropathy. Many compounds have been reported to be advanced glycation end product (AGE) inhibitors such as aminoguanidine, angiotensin II receptor inhibitors and pyridoxamine, and these are useful in therapeutic interventions for reducing AGEs. Pyridoxamine ameliorates lipid peroxidation and insulin resistance in KK-Ay mice. Combination therapy with angiotensin converting inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB), including an ARB and 1,25-dihydroxyvitamin D3, i.e. anti-hypertensive and anti-reactive oxygen species effects, or with eicosapentaenoic acid (EPA), i.e. anti-microinflammation effect, have shown efficacy in the treatment of diabetic nephropathy in KK-Ay mice. It appears that KK-Ay mice are a useful spontaneous animal model for the evaluation of pathogenesis and treatment in patients with type 2 diabetic nephropathy.

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Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial.

Dick de Zeeuw, Rajiv Agarwal, Michael J. Amdahl … (2010)

Despite treatment with renin–angiotensin–aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy. In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks’ treatment with placebo,1 μg/day paricalcitol, or 2 μg/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00421733. Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo(n=93), 1 μg paricalcitol (n=93), or 2 μg paricalcitol (n=95); 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: –3% (from 61 to 60 mg/mmol;95% CI –16 to 13) in the placebo group; –16% (from 62 to 51 mg/mmol; –24 to –9) in the combined paricalcitol groups, with a between-group difference versus placebo of –15% (95% CI –28 to 1; p=0.071); –14% (from 63 to 54 mg/mmol; –24 to –1) in the 1 μg paricalcitol group, with a between-group difference versus placebo of –11%(95% CI –27 to 8; p=0.23); and –20% (from 61 to 49 mg/mmol; –30 to –8) in the 2 μg paricalcitol group, with a between-group difference versus placebo of –18% (95% CI –32 to 0; p=0.053). Patients on 2 μg paricalcitol showed a nearly, sustained reduction in UACR, ranging from –18% to –28% (p=0.014 vs placebo). Incidence of hypercalcaemia,adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo. Addition of 2 μg/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes. Abbott.

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Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure.

Yan Li, Guilin Gary Qiao, Milan Uskokovic … (2004)

The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure, volume and electrolyte homeostasis. Inappropriate activation of the RAS may lead to hypertension. Clinical and epidemiological studies have suggested a correlation between Vitamin D-deficiency and high blood pressure. Our recent studies demonstrate that Vitamin D is a potent endocrine suppressor of renin biosynthesis to regulate the RAS. Mice lacking the Vitamin D receptor (VDR) have elevated production of renin and angiotensin (Ang) II, leading to hypertension, cardiac hypertrophy and increased water intake. These abnormalities can be prevented by treatment with an ACE inhibitor or AT(1) receptor antagonist. Vitamin D repression of renin expression is independent of calcium metabolism, the volume- and salt-sensing mechanisms and the Ang II feedback regulation. In normal mice, Vitamin D-deficiency stimulates renin expression, whereas injection of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] reduces renin synthesis. In cell cultures, 1,25(OH)(2)D(3) directly suppresses renin gene transcription by a VDR-dependent mechanism. Furthermore, we have found that Gemini compounds have more potent renin-suppressing activity than 1,25(OH)(2)D(3). Collectively, our studies reveal a critical role of the Vitamin D endocrine system in the regulation of blood pressure and volume homeostasis, and suggest that low calcemic Vitamin D analogs may potentially be developed into a new class of anti-hypertensive agents to control renin production and blood pressure.

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Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms.

Jonathan Owens, J Kasting, S Wongamorntham … (2005)

Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.

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Author and article information

Journal

Journal ID (nlm-ta): Nephrourol Mon

Journal ID (iso-abbrev): Nephrourol Mon

Journal ID (doi): 10.5812/numonthly

Journal ID (publisher-id): Kowsar

Title: Nephro-urology monthly

Publisher: Kowsar

ISSN (Print): 2251-7006

ISSN (Electronic): 2251-7014

Publication date (Electronic): 20 June 2012

Publication date (Print): Summer 2012

Volume: 4

Issue: 3

Pages: 524-529

Affiliations

[1 ]Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan

Author notes

[* ]Corresponding author: Yasuhiko Tomino, Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, 113-8421, Tokyo, Japan. Tel.: +81-358021064, Fax: +81-338131183, E-mail: yasu@ 123456juntendo.ac.jp

Article

DOI: 10.5812/numonthly.1954

PMC ID: 3614295

PubMed ID: 23573479

SO-VID: 2c350c31-8a4b-40e8-8dd1-2e5124d7e163

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 27 July 2011

Date revision received : 06 September 2011

Date accepted : 15 September 2011

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Lessons From the KK-Ay Mouse, a Spontaneous Animal Model for the Treatment of Human Type 2 Diabetic Nephropathy

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Aging Pathobiology and Therapeutics

Most cited references 31

Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial.

Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure.

Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms.

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