Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

Sugimoto, Hikaru; Grahovac, Gordan; Zeisberg, Michael; Kalluri, Raghu

doi:10.2337/db06-1226

Cited by 203 publications

(182 citation statements)

References 32 publications

(34 reference statements)

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“…In this context, it is notable that B6 mice made diabetic by streptozotocin develop variable degrees of tubulointerstitial fibrosis (11,22). In agreement with this result, we find that our eNOS +/+ Akita diabetic mice developed mild tubulointerstitial fibrosis at age 7 mo (Fig.…”

Section: Discussionsupporting

confidence: 88%

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Wang

Hiller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene ( NOS3 ) have been associated with advanced nephropathy in diabetic patients and with decreased expression in tissue culture. However, direct proof that modest genetic decreases in eNOS expression worsen diabetic nephropathy is lacking. To investigate this effect, we took advantage of the hybrid vigor and genetic uniformity of the F1 progeny (eNOS +/+ , eNOS +/− , or eNOS −/− with or without diabetes) of a cross between heterozygous 129S6/SvEvTac eNOS +/− inbred females and heterozygous C57BL/6J eNOS +/− inbred males carrying the dominant Akita diabetogenic mutation Ins2 C96Y/+ . Whereas all C57BL/6J inbred eNOS −/− and eNOS +/− diabetic mice died before 5 mo, almost half of the F1 hybrid eNOS −/− and eNOS +/− diabetic mice lived until killed at 7 mo. Heterozygous eNOS +/− diabetic mice expressed ∼35% eNOS mRNA in the kidney and ∼25% glomerular eNOS protein relative to their eNOS +/+ diabetic littermates. These decreases in eNOS elevated blood pressure (BP) but not blood glucose. Urinary albumin excretion, mesangial expansion, glomerulosclerosis, mesangiolysis, and glomerular filtration rate increased in the order: eNOS +/+ Akita < eNOS +/− Akita < eNOS −/− Akita, independently of BP. Glomerular basement membrane thickening depended on increased BP. Renal expression of tissue factor and other inflammatory factors increased with the nephropathy; Nos2 also increased. Surprisingly, however, decreased eNOS expression ameliorated the increases in oxidative stress and tubulointerstitial fibrosis caused by diabetes. Our data demonstrate that a modest decrease in eNOS, comparable to that associated with human NOS3 variants, is sufficient to enhance diabetic nephropathy independently of its effects on BP.

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Section: Discussionsupporting

confidence: 88%

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Wang

Hiller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The results demonstrated that strain specific outcomes occur following BSSG exposure that is similar to that following cycad feeding (Wilson et al 2005a). Strain-dependent outcomes have also been noted for streptozotocin treatment (Sugimoto et al 2007), hypoxia (Ward et al 2007), exposure to cannabinoid receptor agonist (Hoffman et al 2005), rinderpest virus (RPV), peste des petits ruminants virus (PPRV) (Galbraith et al 2002), and naloxone (Navarro et al 1991). Although no behavioral deficits were observed in our second in vivo study, there was significant motor neuron loss that was progressive with increasing survival times.…”

Section: Discussionsupporting

confidence: 51%

Chronic Exposure to Dietary Sterol Glucosides is Neurotoxic to Motor Neurons and Induces an ALS–PDC Phenotype

Tabata

Wilson

et al. 2008

Neuromol Med

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Epidemiological studies of the Guamanian variants of amyotrophic lateral sclerosis (ALS) and parkinsonism, amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), have shown a positive correlation between consumption of washed cycad seed flour and disease occurrence. Previous in vivo studies by our group have shown that the same seed flour induces ALS and PDC phenotypes in out bred adult male mice. In vitro studies using isolated cycad compounds have also demonstrated that several of these are neurotoxic, specifically, a number of water insoluble phytosterol glucosides of which β-sitosterol β-D-glucoside (BSSG) forms the largest fraction. BSSG is neurotoxic to motor neurons and other neuronal populations in culture. The present study shows that an in vitro hybrid motor neuron (NSC-34) culture treated with BSSG undergoes a dose-dependent cell loss. Surviving cells show increased expression of HSP70, decreased cytosolic heavy neurofilament expression, and have various morphological abnormalities. CD-1 mice fed mouse NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript chow pellets containing BSSG for 15 weeks showed motor deficits and motor neuron loss in the lumbar and thoracic spinal cord, along with decreased glutamate transporter labelling, and increased glial fibrillary acid protein reactivity. Other pathological outcomes included increased caspase-3 labelling in the striatum and decreased tyrosine-hydroxylase labelling in the striatum and substantia nigra. C57BL/6 mice fed BSSG-treated pellets for 10 weeks exhibited progressive loss of motor neurons in the lumbar spinal cord that continued to worsen even after the BSSG exposure ended. These results provide further support implicating sterol glucosides as one potential causal factor in the motor neuron pathology previously associated with cycad consumption and ALS-PDC.

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“…1F and G). As Sugimoto et al (20) elegantly showed, STZ-induced diabetic CD-1 mice exhibit kidney fibrosis, with both glomerulosclerosis and tubulointerstitial fibrosis occurring ;16 weeks after the onset of diabetes ( Supplementary Fig. 1), and at 24 weeks after the initiation of diabetes, diabetic mice exhibited severe fibrosis when compared with control mice (Fig.…”

Section: Discussionmentioning

confidence: 77%

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

et al. 2014

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Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2–induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.

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Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

Cited by 203 publications

References 32 publications

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Chronic Exposure to Dietary Sterol Glucosides is Neurotoxic to Motor Neurons and Induces an ALS–PDC Phenotype

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

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