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1.
Diabetologia ; 66(1): 223-240, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36260124

RESUMEN

AIMS/HYPOTHESIS: Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting protein (HHIP) was present or specifically knocked out in renal tubules (HhipRT-KO), hypothesising that local deficiency of HHIP in the renal tubules would attenuate tubular cell senescence, thereby preventing DKD tubulopathy. METHODS: Low-dose streptozotocin was employed to induce diabetes in both HhipRT-KO and control (Hhipfl/fl) mice. Transgenic mice overexpressing Hhip in renal proximal tubular cells (RPTC) (HhipRPTC-Tg) were used for validation, and primary RPTCs and human RPTCs (HK2) were used for in vitro studies. Kidney morphology/function, tubular senescence and the relevant molecular measurements were assessed. RESULTS: Compared with Hhipfl/fl mice with diabetes, HhipRT-KO mice with diabetes displayed lower blood glucose levels, normalised GFR, ameliorated urinary albumin/creatinine ratio and less severe DKD, including tubulopathy. Sodium-glucose cotransporter 2 (SGLT2) expression was attenuated in RPTCs of HhipRT-KO mice with diabetes compared with Hhipfl/fl mice with diabetes. In parallel, an increased tubular senescence-associated secretory phenotype involving release of inflammatory cytokines (IL-1ß, IL-6 and monocyte chemoattractant protein-1) and activation of senescence markers (p16, p21, p53) in Hhipfl/fl mice with diabetes was attenuated in HhipRT-KO mice with diabetes. In contrast, HhipRPTC-Tg mice had increased tubular senescence, which was inhibited by canagliflozin in primary RPTCs. In HK2 cells, HHIP overexpression or recombinant HHIP increased SGLT2 protein expression and promoted cellular senescence by targeting both ataxia-telangiectasia mutated and ataxia-telangiectasia and Rad3-related-mediated cell arrest. CONCLUSIONS/INTERPRETATION: Tubular HHIP deficiency prevented DKD-related tubulopathy, possibly via the inhibition of SGLT2 expression and cellular senescence.


Asunto(s)
Proteínas Portadoras , Diabetes Mellitus Tipo 1 , Glicoproteínas de Membrana , Transportador 2 de Sodio-Glucosa , Animales , Humanos , Ratones , Diabetes Mellitus Tipo 1/genética , Células Epiteliales , Proteínas Hedgehog , Transportador 2 de Sodio-Glucosa/genética , Proteínas Portadoras/genética , Glicoproteínas de Membrana/genética , Ratones Transgénicos , Diabetes Mellitus Experimental/genética , Túbulos Renales/citología , Senescencia Celular
2.
Clin Sci (Lond) ; 136(10): 715-731, 2022 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-35502764

RESUMEN

Podocyte damage and loss are the early event in the development of focal segmental glomerulosclerosis (FSGS). Podocytes express angiotensin II type-2-receptor (AT2R), which may play a key role in maintaining kidney integrity and function. Here, we examined the effects of AT2R deletion and AT2R agonist compound 21 (C21) on the evolution of FSGS. FSGS was induced by adriamycin (ADR) injection in both male wild-type (WT) and AT2R knockout (KO) mice. C21 was administered to WT-FSGS mice either one day before or 7 days after ADR (Pre-C21 or Post-C21), using two doses of C21 at either 0.3 (low dose, LD) or 1.0 (high dose, HD) mg/kg/day. ADR-induced FSGS was more severe in AT2RKO mice compared with WT-FSGS mice, and included profound podocyte loss, glomerular fibrosis, and albuminuria. Glomerular cathepsin L expression increased more in AT2RKO-FSGS than in WT-FSGS mice. C21 treatment ameliorated podocyte injury, most significantly in the Pre C21-HD group, and inhibited glomerular cathepsin L expression. In vitro, Agtr2 knock-down in mouse podocyte cell line given ADR confirmed the in vivo data. Mechanistically, C21 inhibited cathepsin L expression, which protected synaptopodin from destruction and stabilized actin cytoskeleton. C21 also prevented podocyte apoptosis. In conclusion, AT2R activation by C21 ameliorated ADR-induced podocyte injury in mice by the inhibition of glomerular cathepsin L leading to the maintenance of podocyte integrity and prevention of podocyte apoptosis.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Enfermedades Renales , Podocitos , Receptor de Angiotensina Tipo 2/metabolismo , Angiotensina II/metabolismo , Animales , Catepsina L/metabolismo , Catepsina L/farmacología , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Imidazoles , Enfermedades Renales/metabolismo , Masculino , Ratones , Ratones Noqueados , Podocitos/metabolismo , Sulfonamidas , Tiofenos
3.
Diabetologia ; 64(9): 2108-2121, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34047808

RESUMEN

AIMS/HYPOTHESIS: The angiotensin II receptor type 2 (AT2R) may be a potential therapeutic target for the treatment of hypertension and chronic kidney disease (CKD). The expression and function of AT2R in the vasculature and kidney appear sexually dimorphic. We hypothesised that Agtr2 knockout dams (AT2RKO) with gestational diabetes would program their offspring for subsequent hypertension and CKD in a sex-dependent manner. METHODS: Age- and sex-matched offspring of non-diabetic and diabetic dams of wild-type (WT) and AT2RKO mice were followed from 4 to 20 weeks of age and were monitored for development of hypertension and nephropathy; a mouse podocyte cell line (mPOD) was also studied. RESULTS: Body weight was progressively lower in female compared with male offspring throughout the lifespan. Female but not male offspring from diabetic AT2RKO dams developed insulin resistance. Compared with the offspring of non-diabetic dams, the progeny of diabetic dams had developed more hypertension and nephropathy (apparent glomerulosclerosis with podocyte loss) at 20 weeks of age; this programming was more pronounced in the offspring of AT2RKO diabetic dams, particularly female AT2RKO progeny. Female AT2RKO offspring had lower basal ACE2 glomerular expression, resulting in podocyte loss. The aberrant ACE2/ACE ratio was far more diminished in glomeruli of female progeny of diabetic AT2RKO dams than in male progeny. Knock-down of Agtr2 in mPODs confirmed the in vivo data. CONCLUSIONS/INTERPRETATION: AT2R deficiency accelerated kidney programming in female progeny of diabetic dams, possibly due to loss of protective effects of ACE2 expression in the kidney.


Asunto(s)
Diabetes Mellitus , Resistencia a la Insulina , Enfermedades Renales , Podocitos , Animales , Femenino , Riñón , Masculino , Ratones
4.
Clin Sci (Lond) ; 135(7): 943-961, 2021 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-33822013

RESUMEN

Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44 mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP.


Asunto(s)
Angiotensina II/farmacología , Enfermedades Renales/fisiopatología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Adulto , Animales , Línea Celular , Femenino , Humanos , Hipertensión/inducido químicamente , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Sistema Renina-Angiotensina/efectos de los fármacos , Transportador 2 de Sodio-Glucosa/genética
5.
J Pathol ; 243(3): 279-293, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28722118

RESUMEN

Angiotensin II type 2 receptor (AT2 R) deficiency in AT2 R knockout (KO) mice has been linked to congenital abnormalities of the kidney and urinary tract; however, the mechanisms by which this occurs are poorly understood. In this study, we examined whether AT2 R deficiency impaired glomerulogenesis and mediated podocyte loss/dysfunction in vivo and in vitro. Nephrin-cyan fluorescent protein (CFP)-transgenic (Tg) and Nephrin/AT2 RKO mice were used to assess glomerulogenesis, while wild-type and AT2 RKO mice were used to evaluate maturation of podocyte morphology/function. Immortalized mouse podocytes (mPODs) were employed for in vitro studies. AT2 R deficiency resulted in diminished glomerulogenesis in E15 embryos, but had no impact on actual nephron number in neonates. Pups lacking AT2 R displayed features of renal dysplasia with lower glomerular tuft volume and podocyte numbers. In vivo and in vitro studies demonstrated that loss of AT2 R was associated with elevated NADPH oxidase 4 levels, which in turn stimulated ectopic hedgehog interacting protein (Hhip) gene expression in podocytes. Consequently, ectopic Hhip expression activation either triggers caspase-3 and p53-related apoptotic processes resulting in podocyte loss, or activates TGFß1-Smad2/3 cascades and α-SMA expression to transform differentiated podocytes to undifferentiated podocyte-derived fibrotic cells. We analyzed HHIP expression in the kidney disease database (Nephroseq) and then validated this using HHIP immunohistochemistry staining of human kidney biopsies (controls versus focal segmental glomerulosclerosis). In conclusion, loss of AT2 R is associated with podocyte loss/dysfunction and is mediated, at least in part, via augmented ectopic Hhip expression in podocytes. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Proteínas Portadoras/metabolismo , Expresión Génica/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glicoproteínas de Membrana/metabolismo , Podocitos/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Adulto , Animales , Proteínas Portadoras/genética , Femenino , Glomeruloesclerosis Focal y Segmentaria/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Ratones Noqueados , Persona de Mediana Edad , Receptor de Angiotensina Tipo 2/deficiencia
6.
Pediatr Res ; 79(3): 416-24, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26571223

RESUMEN

BACKGROUND: The aim of this study was to establish the underlying mechanisms by which a post-weaning high-fat diet (HFD) accelerates the perinatal programming of kidney injury occurring in the offspring of diabetic mothers. METHODS: Male mice, offspring of nondiabetic and diabetic dams were fed with normal diet (ND) or HFD from 4 to 20 wk of age. Rat renal proximal tubular cells were used in vitro. RESULTS: On ND, the offspring of dams with severe maternal diabetes had an intrauterine growth restriction (IUGR) phenotype and developed mild hypertension and evidence of kidney injury in adulthood. Exposing the IUGR offspring to HFD resulted in rapid weight gain, catch-up growth, and later to profound kidney injury with activation of renal TGFß1 and collagen type IV expression, increased oxidative stress, and enhanced renal lipid deposition, but not systemic hypertension. Given our data, we speculate that HFD or free fatty acids may accelerate the process of perinatal programming of kidney injury, via increased CD36 and fatty acid-binding protein 4 expression, which may target reactive oxygen species, nuclear factor-kappa B, and TGFß1 signaling in vivo and in vitro. CONCLUSION: Early postnatal exposure to overnutrition with a HFD increases the risk of development of kidney injury, but not hypertension, in IUGR offspring of dams with maternal diabetes.


Asunto(s)
Diabetes Gestacional/fisiopatología , Dieta Alta en Grasa/efectos adversos , Hipertensión/fisiopatología , Riñón/fisiopatología , Animales , Apoptosis , Peso Corporal , Antígenos CD36/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Femenino , Retardo del Crecimiento Fetal/fisiopatología , Prueba de Tolerancia a la Glucosa , Hipertensión/complicaciones , Riñón/lesiones , Enfermedades Renales/complicaciones , Enfermedades Renales/inmunología , Túbulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Fenotipo , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Destete
7.
Diabetologia ; 57(9): 1986-96, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24957663

RESUMEN

AIMS/HYPOTHESIS: We hypothesised that maternal diabetes impairs kidney formation in offspring via augmented expression of hedgehog interacting protein (HHIP). Our gene-array results were performed in neonatal kidneys from our murine model of maternal diabetes and indicated that Hhip expression was significantly modulated by maternal diabetes. METHODS: We systematically examined the functional role of HHIP in kidney formation in our murine maternal diabetes model and elucidated the potential mechanisms related to dysnephrogenesis in vitro. RESULTS: The kidneys of the offspring of diabetic dams, compared with those of the offspring of control non-diabetic dams, showed retardation of development--small kidneys and less ureteric bud (UB) branching morphogenesis. Augmented HHIP expression was observed in the offspring of diabetic dams, initially localised to differentiated metanephric mesenchyme and UB epithelium and subsequently in maturing glomerular endothelial and tubulointerstitial cells. The heightened HHIP targeting TGF-ß1 signalling was associated with dysmorphogenesis. In vitro, HHIP overexpression decreased sonic hedgehog and paired box gene 2 proteins (SHH and PAX2, respectively) and increased transcriptional nuclear factor-kappa B (NFκB, p50/p65), phosphorylation of p53, and TGF-ß1 expression. In contrast, overexpression of PAX2 inhibited HHIP and NFκB and activated SHH, N-myc and p27(Kip1) expression. Moreover, high glucose stimulated HHIP expression, and then targeted TGF-ß1 signalling. Thus, PAX2, via a negative autocrine feedback mechanism, attenuated the stimulatory effect of high glucose on HHIP expression. CONCLUSIONS/INTERPRETATION: Maternal diabetes modulates kidney formation in young progeny mediated, at least in part, via augmented HHIP expression.


Asunto(s)
Proteínas Portadoras/metabolismo , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatología , Riñón/embriología , Riñón/metabolismo , Glicoproteínas de Membrana/metabolismo , Animales , Femenino , Ratones , Embarazo
8.
Transl Res ; 267: 1-9, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38195017

RESUMEN

Heterogeneous nuclear ribonucleoprotein F (HnRNP F) is a key regulator for nucleic acid metabolism; however, whether HnRNP F expression is important in maintaining podocyte integrity is unclear. Nephroseq analysis from a registry of human kidney biopsies was performed. Age- and sex-matched podocyte-specific HnRNP F knockout (HnRNP FPOD KO) mice and control (HnRNP Ffl/fl) were studied. Podocytopathy was induced in male mice (more susceptible) either by adriamycin (ADR)- or low-dose streptozotocin treatment for 2 or 8 weeks. The mouse podocyte cell line (mPODs) was used in vitro. Nephroseq data in three human cohorts were varied greatly. Both sexes of HnRNP FPOD KO mice were fertile and appeared grossly normal. However, male 20-week-old HnRNP FPOD KO than HnRNP Ffl/fl mice had increased urinary albumin/creatinine ratio, and lower expression of podocyte markers. ADR- or diabetic- HnRNP FPOD KO (vs. HnRNP Ffl/fl) mice had more severe podocytopathy. Moreover, methyltransferase-like 14 (Mettl14) gene expression was increased in podocytes from HnRNP FPOD KO mice, further enhanced in ADR- or diabetic-treated HnRNP FPOD KO mice. Consequently, this elevated Mettl14 expression led to sirtuin1 (Sirt1) inhibition, associated with podocyte loss. In mPODs, knock-down of HnRNP F promoted Mettl14 nuclear translocation, which was associated with podocyte dysmorphology and Sirt1 inhibition-mediated podocyte loss. This process was more severe in ADR- or high glucose- treated mPODs. Conclusion: HnRNP F deficiency in podocytes promotes podocytopathy through activation of Mettl14 expression and its nuclear translocation to inhibit Sirt1 expression, underscoring the protective role of HnRNP F against podocyte injury.


Asunto(s)
Diabetes Mellitus , Podocitos , Femenino , Ratones , Masculino , Humanos , Animales , Podocitos/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/metabolismo , Diabetes Mellitus/metabolismo , Metiltransferasas/metabolismo
9.
Antioxidants (Basel) ; 12(9)2023 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-37760019

RESUMEN

The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2 diabetes (T2D) db/db mice (db/dbNrf2 knockout (KO)) attenuates DKD progression through the down-regulation of angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), and lipid accumulation in renal proximal tubular cells (RPTCs). Db/dbNrf2 KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with NRF2 KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/dbNrf2 KO mice had lower systolic blood pressure, fasting blood glucose, kidney hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, tubular lipid droplet accumulation, and decreased expression of AGT, SGLT2, CD36, and FABP4 in RPTCs. Male and female mice had similar results. NRF2 KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D.

10.
J Cell Physiol ; 227(1): 108-15, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21374590

RESUMEN

O-linked N-acetylglucosamine (O-GlcNAc) protein modification has been implicated in the regulation of signaling pathways, cell function, and gene expression. Glutamine:fructose-6-phosphate amidotransferase-1 (GFAT-1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), which generates the sugar nucleotide UDP-GlcNAc, where this nucleotide acts as the donor for O-GlcNAc modification. In this study, we determined whether GFAT-1 regulates adipogenesis in adipocytes. 3T3-L1 preadipocytes were differentiated using medium containing high glucose, insulin, dexamethasone, and isobutylmethylxanthine. Cells were harvested 4, 8, and 12 h and 1, 2, 3, 4, 6, and 8 days after the initiation of differentiation. Global level of O-GlcNAc modification increased 4 h after induction and persisted for 8 days of observation. GFAT-1 mRNA and protein expression was also upregulated beginning 4 h after induction. Pharmacological inhibition of GFAT-1 or GFAT-1 siRNA treatment blocked the increase in O-GlcNAcylation and the formation of lipid droplets in adipocytes. GFAT-1 may regulate the expression of C/EBPß, PPARγ, SREBP-1, fatty acid synthase, S3-12, perilipin, or adipophilin during adipogenesis. Our results suggest that GFAT-1 plays a critical role in modulating adipogenesis via the regulation of protein O-GlcNAcylation in adipocytes.


Asunto(s)
Adipocitos/metabolismo , Adipogénesis/fisiología , Regulación de la Expresión Génica/fisiología , Transferasas de Grupos Nitrogenados/metabolismo , Transducción de Señal/fisiología , Acetilación , Adipocitos/citología , Animales , Western Blotting , Diferenciación Celular/fisiología , Línea Celular , Expresión Génica/fisiología , Glutamina/metabolismo , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora) , Inmunoprecipitación , Ratones , Procesamiento Proteico-Postraduccional/fisiología , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa
11.
Plants (Basel) ; 11(10)2022 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-35631770

RESUMEN

Species distribution modeling (SDM) is currently the primary tool for predicting suitable habitats for species. In this study, we used Abies kawakamii, a species endemic to Taiwan. Being the only Abies species distributed in high mountains, it acts as an ecological indicator on the subtropical island. We analyzed a vegetation map derived from remote sensing and ground surveys using SDM. The actual distribution of A. kawakamii in Taiwan has a total area of 16,857 ha distributed at an altitude of 2700-3600 m, and it often forms a monodominant forest at 3100-3600 m with the higher altitude edge as a forest line. Exploring the potential distribution of A. kawakamii through MaxEnt showed that the suitable habitat was 73,151 ha under the current climate. Under the scenarios of temperature increases of 0.5, 1.0, 1.5, and 2.0 °C, suitable habitat for A. kawakamii will gradually decrease to 70.2%, 47.1%, 30.2%, and 10.0% of this area, respectively, indicating that A. kawakamii will greatly decline under these climate warming scenarios. Fire burning disturbance may be the most significant damage to A. kawakamii at present. Although A. kawakamii has been protected by conservation areas and its natural regeneration is in good condition, it rarely has the opportunity to migrate upwards during climate warming. We suggest that in the future, research on the natural regeneration and artificial restoration of A. kawakamii should be emphasized, especially in the forest line ecotone.

12.
PLoS One ; 16(7): e0254791, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34293040

RESUMEN

The spatial patterns of plant species reflect the competitive pressures on individuals. To generate Competition indices (CI), we measured the diameter at breast height (DBH), crown volumes (CV) and the distances between trees. In this study, Abies kawakamii were divided based on the dominant component of the understory (moss or bamboo) to (1) investigate the relationship between the CI and stand structural attributes (SSAs); (2) compare the inter- and intraspecies; CIs as well as living and dead individual CIs; and (3) examine the relationship between the DBH and CI. The current findings indicate that the understory composition affected the CI and SSAs. The interspecies CI was larger than the intraspecies CI when bamboo-dominated the understory. In contrast, the intraspecies CI was larger than the interspecies CI when the understory was dominated by moss. The CI of dead individuals was higher than that of live individuals due to the biological characteristics and regeneration needs of Abies. Additionally, sensitivity to the environment and available resources may exert more pressure on young individuals than mature individuals.


Asunto(s)
Abies/crecimiento & desarrollo , Conservación de los Recursos Naturales , Bosques , Taiwán
13.
Transl Res ; 217: 1-10, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31794697

RESUMEN

Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1ß, IL-6, IL-8, and TGFß1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFß1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.


Asunto(s)
Proteínas Portadoras/orina , Nefropatías Diabéticas/orina , Glicoproteínas de Membrana/orina , Adulto , Anciano , Albuminuria/orina , Animales , Creatinina/orina , Células Endoteliales/patología , Femenino , Humanos , Riñón/química , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Estudios Prospectivos , Factor de Crecimiento Transformador beta1/análisis
14.
Sci Rep ; 9(1): 11183, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31371780

RESUMEN

Hedgehog interacting protein (Hhip) is essential for islet formation and beta-cell proliferation during pancreatic development; abnormally elevated Hhip expression has been linked to human pancreatitis. Here, we investigate the role of Hhip in modulating insulin secretion in adult Hhip mice (Hhip +/- vs. Hhip+/+) fed high fat diets (HFD). Both sexes of HFD-Hhip +/+ mice developed impaired glucose intolerance, that was only ameliorated in male HFD-Hhip +/- mice that had high levels of circulating plasma insulin, but not in female HFD-Hhip +/- mice. HFD stimulated Hhip gene expression, mainly in beta cells. Male HFD-Hhip +/+ mice had more large islets in which insulin content was reduced; islet architecture was disordered; and markers of oxidative stress (8-OHdG and Nox 2) were increased. In contrast, male HFD-Hhip +/- mice had more small islets with increased beta cell proliferation, enhanced GSIS, less oxidative stress and preserved islet integrity. In vitro, recombinant Hhip increased Nox2 and NADPH activity and decreased insulin-positive beta cells. siRNA-Hhip increased GSIS and abolished the stimulation of sodium palmitate (PA)-BSA on Nox2 gene expression. We conclude that pancreatic Hhip gene inhibits insulin secretion by altering islet integrity and promoting Nox2 gene expression in beta cells in response to HDF-mediated beta cell dysfunction, a novel finding.


Asunto(s)
Glucemia/metabolismo , Proteínas Portadoras/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Intolerancia a la Glucosa/metabolismo , Secreción de Insulina/fisiología , Glicoproteínas de Membrana/metabolismo , Animales , Glucemia/análisis , Proteínas Portadoras/genética , Línea Celular , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/etiología , Heterocigoto , Insulina/sangre , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Transgénicos , Estrés Oxidativo , Cultivo Primario de Células , ARN Interferente Pequeño/metabolismo , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores Sexuales
15.
Sci Rep ; 8(1): 5958, 2018 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-29654303

RESUMEN

We investigated whether renal hedgehog interacting protein (Hhip) expression contributes to the progression of diabetic nephropathy (DN) and studied its related mechanism(s) in vivo and in vitro. Here, we show that Hhip expression is highly elevated in glomerular endothelial cells of adult type 1 diabetic (T1D) Akita and T2D db/db mouse kidneys as compared to non-diabetic control littermates. Hyperglycemia enhances reactive oxygen species (ROS) generation via NADPH oxidase 4 (Nox4) activation and stimulates renal Hhip gene expression, and that elevated renal Hhip gene expression subsequently activates the TGFß1- Smad2/3 cascade and promotes endothelial to mesenchymal transition associated with endothelial cell fibrosis/apoptosis in vivo and in vitro. Furthermore, kidneys of low-dose streptozotocin-induced diabetic heterozygous Hhip deficient (Hhip+/-) mice displayed a normal albumin/creatinine ratio with fewer features of DN (glomerulosclerosis/fibrosis and podocyte apoptosis/loss) and less evidence of renal compensation (glomerular hypertrophy and hyperfiltration) as compared to diabetic wild type controls (Hhip+/+). Thus, our studies demonstrated that renal Hhip expression is associated with nephropathy development in diabetes and that hyperglycemia-induced renal Hhip expression may mediate glomerular endothelial fibrosis and apoptosis in diabetes, a novel finding.


Asunto(s)
Apoptosis/fisiología , Proteínas Portadoras/metabolismo , Diabetes Mellitus Experimental/metabolismo , Células Endoteliales/metabolismo , Fibrosis/metabolismo , Glomérulos Renales/metabolismo , Glicoproteínas de Membrana/metabolismo , Albúminas/metabolismo , Animales , Creatinina/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Fibrosis/inducido químicamente , Fibrosis/patología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 4/metabolismo , Podocitos/metabolismo , Podocitos/fisiología , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina/farmacología , Factor de Crecimiento Transformador beta1/metabolismo
16.
Artículo en Inglés | MEDLINE | ID: mdl-27638854

RESUMEN

INTRODUCTION: We aimed to examine the regulation of aquaporin 1 expression in an angiotensinogen transgenic mouse model, focusing on underlying mechanisms. METHODS: Male transgenic mice overexpressing rat angiotensinogen in their renal proximal tubular cells (RPTCs) and rat immortalised RPTCs stably transfected with rat angiotensinogen cDNA were used. RESULTS: Angiotensinogen-transgenic mice developed hypertension and nephropathy, changes that were either partially or completely attenuated by treatment with losartan or dual renin-angiotensin system blockade (losartan and perindopril), respectively, while hydralazine prevented hypertension but not nephropathy. Decreased expression of aquaporin 1 and heme oxygenase-1 and increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and sodium-hydrogen exchanger 3 were observed in RPTCs of angiotensinogen-transgenic mice and in angiotensinogen-transfected immortalised RPTCs. These parameters were normalised by dual renin-angiotensin system blockade. Both in vivo and in vitro studies identified a novel mechanism in which angiotensinogen overexpression in RPTCs enhances the cytosolic accumulation of Nrf2 via the phosphorylation of pGSK3ß Y216. Consequently, lower intranuclear Nrf2 levels are less efficient to trigger heme oxygenase-1 expression as a defence mechanism, which subsequently diminishes aquaporin 1 expression in RPTCs. CONCLUSIONS: Angiotensinogen-mediated downregulation of aquaporin 1 and Nrf2 signalling may play an important role in intrarenal renin-angiotensin system-induced hypertension and kidney injury.


Asunto(s)
Angiotensinógeno/metabolismo , Acuaporina 1/genética , Regulación hacia Abajo , Hemo-Oxigenasa 1/metabolismo , Túbulos Renales Proximales/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Animales , Acuaporina 1/metabolismo , Línea Celular , Proteínas de la Matriz Extracelular/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Inmunohistoquímica , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Túbulos Renales Proximales/patología , Ratones Transgénicos , Modelos Biológicos , Fosforilación , Ratas , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , beta Catenina/metabolismo
17.
Food Chem Toxicol ; 50(3-4): 779-89, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22222928

RESUMEN

Toona sinensis Roem (T. sinensis) leaves have been used as a nutritious vegetable and been suggested for medical applications; however, the reported bioactive compounds of T. sinensis leaves are, so far, from high to mid-high polar extracts. Our aims in this study were to reveal the non-polar constituents of the T. sinensis leave extract that were prepared by a method of using a supercritical-CO2 fluid and to investigate the anti-diabetic potential of this extract. Through a GC/MS analysis, we revealed 24 major components of the non-polar T. sinensis leave extract, the most abundant of which was phytol. The non-polar T. sinensis leave extract showed to prevent the progression of diabetes and hepatosteatosis, the rise of triglycerol levels and the decrease of adiponectin levels in the type 2 diabetic mice. Our results suggest that the non-polar extract of T. sinensis leaves prepared using the supercritical-CO2 fluid may contain effective constituents to prevent type 2 diabetes.


Asunto(s)
Cromatografía con Fluido Supercrítico , Hipoglucemiantes/farmacología , Meliaceae/química , Extractos Vegetales/farmacología , Células 3T3-L1 , Animales , Dióxido de Carbono/química , Cromatografía de Gases y Espectrometría de Masas , Masculino , Ratones , Ratones Endogámicos C57BL
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