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Li W, Xu G, Li M. Diabetic kidney disease: m6A modification as a marker of disease progression and subtype classification. Front Med (Lausanne) 2025; 12:1494162. [PMID: 40103797 PMCID: PMC11914134 DOI: 10.3389/fmed.2025.1494162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/14/2025] [Indexed: 03/20/2025] Open
Abstract
This paper aims to investigate m6A modification during DKD progression. We evaluated m6A regulators expression in peripheral blood mononuclear cells, whole kidney tissue, glomerular, and tubulointerstitial samples. CIBERSORT and single-sample gene set enrichment analysis analyzed glomerular immune characteristics. Logistic-LASSO regression were used to develop the m6A regulators model that can identify early DKD. Consensus clustering algorithms were used to classify DKD in glomerular samples into m6A modified subtypes based on the expression of m6A regulators. Gene set variation analysis algorithm was used to evaluate the functional pathway enrichment of m6A modified subtypes. Weighted gene co-expression network analysis and protein-protein interaction networks identified m6A modified subtype marker genes. The Nephroseq V5 tool was used to evaluate the correlation between m6A modified subtypes marker genes and renal function. DKD patients' m6A regulators expression differed from the control group in various tissue types. DKD stages have various immune characteristics. The m6A regulators model with YTHDC1, METTL3, and ALKBH5 better identified early DKD. DKD was divided into two subtypes based on the expression of 26 m6A regulators. Subtype 1 was enriched in myogenesis, collagen components, and cytokine receptor interaction, while subtype 2 was enriched in protein secretion, proliferation, apoptosis, and various signaling pathways (e.g., TGFβ signaling pathway, PI3K/AKT/mTOR pathway, and etc.). Finally, AXIN1 and GOLGA4 were identified as possible biomarkers associated with glomerular filtration rate. From the viewpoint of m6A modification, the immune characteristics and molecular mechanisms of DKD at various stages are different, and targeted treatment would improve efficacy.
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Affiliation(s)
- Wenzhe Li
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Gaosi Xu
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Manna Li
- Department of Nephrology, Second Affiliated Hospital of Nanchang University, Nanchang, China
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Gonzalez AA, Visniauskas B, Reverte V, Sure VN, Vallotton Z, Torres BS, Acosta MA, Zemedkun M, Katakam PV, Prieto MC. Urinary Angiotensinogen Displays Sexual Dimorphism in Non-Diabetic Humans and Mice with Overweight. Int J Mol Sci 2024; 25:635. [PMID: 38203807 PMCID: PMC10779427 DOI: 10.3390/ijms25010635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/28/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Increased body weight (BW) induces inappropriate renin-angiotensin system (RAS) activation. The activation of the intrarenal RAS is associated with increased urinary angiotensinogen (uAGT), blood pressure (BP), and kidney damage. Here, we examined uAGT excretion levels in young non-diabetic human subjects with overweight (OW) and non-diabetic mice with high-fat diet (HFD)-induced OW. Human subjects (women and men; 20-28 years old) included two groups: (a) overweight (OW, n = 17, BMI ≥ 25); and (b) controls (normal weight (NW; n = 26, BMI ≤ 25). In these subjects, we measured BP, albuminuria, and protein levels of uAGT by ELISA adjusted by urinary creatinine (expressed by uAGT/uCrea). Mice (female and male C57BL/6J mice, 8 ± 2 weeks of age) also included two groups: HFD or normal fat diet (NFD) fed for 8 weeks. We measured BW, fasting blood glucose (FBG), BP by telemetry, albuminuria, and uAGT by ELISA. In humans: (i) no significant changes were observed in BP, albuminuria, and FBG when comparing NW and OW subjects; (ii) multivariate logistic regression analysis of independent predictors related to uAGT/uCrea levels demonstrated a strong association between uAGT and overweight; (iii) urinary reactive oxygen species (ROS) were augmented in men and women with OW; (iv) the uAGT/uCrea ratio was higher in men with OW. However, the uAGT/uCrea values were lower in women even with OW. In mice: (i) males fed an HFD for 8 weeks became OW while females did not; (ii) no changes were observed either in FBG, BP, or albuminuria; (iii) kidney ROS were augmented in OW male mice after 28 weeks but not in females; (iv) OW male mice showed augmented excretion of uAGT but this was undetectable in females fed either NFD or HFD. In humans and mice who are OW, the urinary excretion of AGT differs between males and females and overcomes overt albuminuria.
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Affiliation(s)
- Alexis A. Gonzalez
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340025, Chile
| | - Bruna Visniauskas
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Virginia Reverte
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Ventaka N. Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Zoe Vallotton
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Bryan S. Torres
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Marco A. Acosta
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Mahlet Zemedkun
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Prasad V. Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Minolfa C. Prieto
- Department of Physiology and Hypertension Core, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Renal and Hypertension Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Kulthinee S, Tasanarong A, Franco M, Navar LG. Interaction of Angiotensin II AT1 Receptors with Purinergic P2X Receptors in Regulating Renal Afferent Arterioles in Angiotensin II-Dependent Hypertension. Int J Mol Sci 2023; 24:11413. [PMID: 37511174 PMCID: PMC10380633 DOI: 10.3390/ijms241411413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/09/2023] [Indexed: 07/30/2023] Open
Abstract
In angiotensin II (Ang II)-dependent hypertension, Ang II activates angiotensin II type 1 receptors (AT1R) on renal vascular smooth muscle cells, leading to renal vasoconstriction with eventual glomerular and tubular injury and interstitial inflammation. While afferent arteriolar vasoconstriction is initiated by the increased intrarenal levels of Ang II activating AT1R, the progressive increases in arterial pressure stimulate the paracrine secretion of adenosine triphosphate (ATP), leading to the purinergic P2X receptor (P2XR)-mediated constriction of afferent arterioles. Thus, the afferent arteriolar tone is maintained by two powerful systems eliciting the co-existing activation of P2XR and AT1R. This raises the conundrum of how the AT1R and P2XR can both be responsible for most of the increased renal afferent vascular resistance existing in angiotensin-dependent hypertension. Its resolution implies that AT1R and P2XR share common receptor or post receptor signaling mechanisms which converge to maintain renal vasoconstriction in Ang II-dependent hypertension. In this review, we briefly discuss (1) the regulation of renal afferent arterioles in Ang II-dependent hypertension, (2) the interaction of AT1R and P2XR activation in regulating renal afferent arterioles in a setting of hypertension, (3) mechanisms regulating ATP release and effect of angiotensin II on ATP release, and (4) the possible intracellular pathways involved in AT1R and P2XR interactions. Emerging evidence supports the hypothesis that P2X1R, P2X7R, and AT1R actions converge at receptor or post-receptor signaling pathways but that P2XR exerts a dominant influence abrogating the actions of AT1R on renal afferent arterioles in Ang II-dependent hypertension. This finding raises clinical implications for the design of therapeutic interventions that will prevent the impairment of kidney function and subsequent tissue injury.
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Affiliation(s)
- Supaporn Kulthinee
- Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Adis Tasanarong
- Chulabhorn International College of Medicine, Thammasat University, Klong Luang 12120, Thailand
| | - Martha Franco
- Department of Cardio-Renal Physiopathology, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico
| | - Luis Gabriel Navar
- Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Cornejo MA, Jardines E, Nishiyama A, Nakano D, Ortiz RM. Simultaneous SGLT2 inhibition and caloric restriction improves insulin resistance and kidney function in OLETF rats. Mol Cell Endocrinol 2023; 560:111811. [PMID: 36397615 DOI: 10.1016/j.mce.2022.111811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 11/08/2022]
Abstract
SGLT2 inhibitors (SGLT2i) are emerging as a novel therapy for type 2 diabetes due to their effective hypoglycemic and potential cardio- and nephroprotective effects, while caloric restriction (CR) is a common behavioral modification to improve adiposity and insulin resistance. Therefore, both interventions simultaneously may potentially further improve metabolic syndrome by enhancing carbohydrate metabolism. To test this hypothesis, cohorts of 10-week old, male Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were treated with SGLT2i (10 mg luseoglifozin/kg/day x 4 wks) (OLETF only) and/or 30% CR (2 wks at 12 weeks of age). CR maintained body mass in both strains while SGLT2i alone did not have any effect on body mass. Simultaneous treatments decreased SBP in OLETF vs SGLT2i alone, decreased insulin resistance index (IRI), and increased creatinine clearance vs OLETF ad lib. Conversely, CR decreased albuminuria independent of SGLT2i. In conclusion, SGLT2i treatment by itself did not elicit significant improvements in insulin resistance, kidney function or blood pressure. However, when combined with CR, these changes where more profound than with CR alone without inducing chronic hypoglycemia.
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Affiliation(s)
- Manuel A Cornejo
- Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.
| | - Eira Jardines
- Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Rudy M Ortiz
- Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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6
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De Bhailis ÁM, Kalra PA. Hypertension and the kidneys. Br J Hosp Med (Lond) 2022; 83:1-11. [DOI: 10.12968/hmed.2021.0440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hypertension is a leading risk factor for cardiovascular disease and all-cause mortality globally. Hypertension and chronic kidney disease are closely intertwined conditions as hypertension can lead to deteriorating renal function and progressive chronic kidney disease can contribute to worsening hypertension. In the setting of chronic kidney disease, the pathophysiology of hypertension is complex and involves the interplay of many factors including a reduced number of functioning nephrons, sodium retention and volume expansion, upregulation of the sympathetic nervous system, hormonal factors such as upregulation of the renin–angiotensin–aldosterone system, and endothelial dysfunction. Poorly controlled hypertension can accelerate the progression to end-stage kidney disease. This review discusses the pathophysiological mechanisms that contribute to hypertension, including sympathetic nervous system activity, the renin–angiotensin–aldosterone system and the role of sodium. In the setting of chronic kidney disease, the relationship with hypertension and renovascular disease as a potential cause and target for therapeutic intervention is briefly reviewed. Finally, treatment options, targets and the long-term cardiovascular benefits of optimal blood pressure control are discussed.
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Affiliation(s)
- Áine M De Bhailis
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
| | - Philip A Kalra
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
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Lin JR, Wang ZT, Sun JJ, Yang YY, Li XX, Wang XR, Shi Y, Zhu YY, Wang RT, Wang MN, Xie FY, Wei P, Liao ZH. Gut microbiota and diabetic kidney diseases: Pathogenesis and therapeutic perspectives. World J Diabetes 2022; 13:308-318. [PMID: 35582668 PMCID: PMC9052008 DOI: 10.4239/wjd.v13.i4.308] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/09/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the major chronic complications of diabetes mellitus (DM), as well as a main cause of end-stage renal disease. Over the last few years, substantial research studies have revealed a contributory role of gut microbiota in the process of DM and DKD. Metabolites of gut microbiota like lipopolysaccharide, short-chain fatty acids, and trimethylamine N-oxide are key mediators of microbial–host crosstalk. However, the underlying mechanisms of how gut microbiota influences the onset and progression of DKD are relatively unknown. Besides, strategies to remodel the composition of gut microbiota or to reduce the metabolites of microbiota have been found recently, representing a new potential remedial target for DKD. In this mini-review, we will address the possible contribution of the gut microbiota in the pathogenesis of DKD and its role as a therapeutic target.
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Affiliation(s)
- Jia-Ran Lin
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Nephrology and Endocrinology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Zi-Ting Wang
- Department of Environmental Medicine, Karolinska Institutet, Stockholm 17165, Sweden
| | - Jiao-Jiao Sun
- First Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ying-Ying Yang
- Clinical Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna 17165, Sweden
| | - Xue-Xin Li
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17121, Sweden
| | - Xin-Ru Wang
- Department of Acupuncture and Moxibustion, First Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yue Shi
- Second Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yuan-Yuan Zhu
- First Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Rui-Ting Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mi-Na Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China
| | - Fei-Yu Xie
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Oncology, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Peng Wei
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ze-Huan Liao
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm 17177, Sweden
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8
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Godoy-Lugo JA, Thorwald MA, Hui DY, Nishiyama A, Nakano D, Soñanez-Organis JG, Ortiz RM. Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats. Endocrine 2022; 75:92-107. [PMID: 34327606 PMCID: PMC8763929 DOI: 10.1007/s12020-021-02834-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/18/2021] [Indexed: 11/01/2022]
Abstract
PURPOSE Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS. METHODS Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose). RESULTS Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB. CONCLUSIONS Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.
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Affiliation(s)
- Jose A Godoy-Lugo
- School of Natural Sciences, University of California, Merced, CA, USA.
| | - Max A Thorwald
- School of Natural Sciences, University of California, Merced, CA, USA
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - David Y Hui
- Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
| | - Jose G Soñanez-Organis
- Universidad de Sonora, Departamento de Ciencias Químico Biológicas y Agropecuarias, Navojoa, Sonora, Mexico
| | - Rudy M Ortiz
- School of Natural Sciences, University of California, Merced, CA, USA
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Ambinathan JPN, Sridhar VS, Lytvyn Y, Lovblom LE, Liu H, Bjornstad P, Perkins BA, Lovshin JA, Cherney DZI. Relationships between inflammation, hemodynamic function and RAAS in longstanding type 1 diabetes and diabetic kidney disease. J Diabetes Complications 2021; 35:107880. [PMID: 33678512 DOI: 10.1016/j.jdiacomp.2021.107880] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 11/24/2022]
Abstract
The renin angiotensin aldosterone system (RAAS) is associated with renal disease and inflammation in a diabetes setting, however, little is known about the implicated mechanisms in individuals with long standing diabetes. Accordingly, our aim was to perform an observational study to quantify urinary excretion of inflammatory biomarkers in participants with long standing type 1 diabetes (T1D) (with and without diabetic kidney disease [DKD]) and controls, at baseline and in response to RAAS activation. GFRINULIN, ERPFPAH, and 42 urine inflammatory biomarkers were measured in 74 participants with T1D for ≥50 years (21 with DKD and 44 without DKD [DKD resistors]) and 73 healthy controls. Additionally, inflammatory biomarkers were measured before and after an angiotensin II infusion (ANGII, 1 ng∙kg-1∙min-1). Significantly lower urinary excretion of cytokines (IL-18, IL-1RA, IL-8), chemokines (MCP1, RANTES) and growth factors (TGF-α, PDGFAA, PDGFBB, VEGF-A) was observed in participants with T1D at baseline compared to controls. Urinary IL-6 was higher in DKD than in DKD resistors in an exploratory analysis unadjusted for multiple comparisons. In T1D only, lower GFRINULIN correlated with greater excretion of proinflammatory biomarkers (IL-18, IP-10, & RANTES), growth factors (PDGF-AA & VEGFAA), and chemokines (eotaxin & MCP-1). ANGII increased 31 of 42 inflammatory biomarkers in T1D vs controls (p < 0.05), regardless of DKD resistor status. In conclusion, lower GFR and intra-renal RAAS activation were associated with increased inflammation even after longstanding T1D. The increased urinary IL-6 in patients with DKD requires further investigation to determine whether IL-6 is a candidate protective biomarker for prognostication or targeted therapy in DKD.
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Affiliation(s)
| | - Vikas S Sridhar
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leif Erik Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Hongyan Liu
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Department of Pediatrics, Section of Endocrinology, Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA
| | - Bruce A Perkins
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, Toronto, Canada
| | - Julie A Lovshin
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, Toronto, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, Toronto, Canada.
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10
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Li L, Wang C, Gu Y. Collagen IV, a promising serum biomarker for evaluating the prognosis of revascularization in a 2-kidney, 1-clip hypertensive rat model. Interact Cardiovasc Thorac Surg 2020; 30:483-490. [PMID: 31725159 DOI: 10.1093/icvts/ivz275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 09/25/2019] [Accepted: 10/10/2019] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES The goal of this study was to investigate the expression of serum collagen IV and its value for evaluating the prognosis of revascularization in a 2-kidney, 1-clip hypertensive rat model. METHODS A total of 40 Sprague-Dawley rats were randomly and evenly divided into a control group and 3-, 10- and 20-day (D) groups (namely, the ischaemic time for 3, 10 and 20 days, respectively). The systolic blood pressure and laboratory values such as serum creatinine and collagen IV levels were measured before and after clipping the renal artery. Histological Masson staining and immunohistochemical staining of collagen IV were conducted in a kidney specimen from each group to assess the severity of renal fibrosis and the level of collagen IV expression. RESULTS After clipping, systolic blood pressure in the 3D, 10D and 20D groups increased significantly from 108 ± 8 to 126 ± 7 and from 153 ± 8 to 157 ± 6 mmHg, respectively (10D vs 20D group, P = 0.224; between other groups, P < 0.001). The expression of serum creatinine in the 3D, 10D and 20D groups increased significantly from 35.39 ± 5.64 to 57.53 ± 7.05, 101.86 ± 8.94 and 119.76 ± 9.37 mmol/l, respectively (between each group: P < 0.001). Serum collagen IV levels in the 10D and 20D groups increased significantly from 38.5 ± 10.4 to 60.8 ± 15.0 and 87.3 ± 11.5 ng/ml, respectively (control vs 3D group, P = 0.718; between other groups, P < 0.001). The Masson staining indicated that sclerotic changes in the glomeruli of the 10D and 20D groups significantly increased from 2.20 ± 1.03 to 15.20 ± 5.03 and 28.20 ± 7.07%, respectively (control vs 3D group, P = 0.175; between other groups, P < 0.001). The grade of tubulointerstitial damage in the 3D, 10D and 20D groups increased significantly from 0.30 ± 0.48 to 1.90 ± 0.74, 1.80 ± 0.79 and 3.20 ± 0.79, respectively (3D vs 10D group, P = 0.755; between other groups, P < 0.001). The semi-quantification from immunohistochemical staining indicated that the percentage of collagen IV positive areas in the 3D, 10D and 20D groups increased significantly from 3.50 ± 1.58 to 8.60 ± 2.11, 16.60 ± 8.55 and 23.10 ± 6.15, respectively (control vs 3D group, P = 0.043; 3D vs 10D group, P = 0.002; 10D vs 20D group, P = 0.011; between other groups, P < 0.001). The area under the curve of the receiver operating characteristic curve was 0.783 (P = 0.008; 95% confidence interval 0.634-0.932). There were positive associations of serum collagen IV levels with systolic blood pressure, serum creatinine and collagen IV quantification in kidney with correlation coefficients of 0.665, 0.775 and 0.628, respectively (P < 0.001). CONCLUSIONS As the clear ischaemia time-response relationship identified in our study indicates, the increase in serum collagen IV levels may be a satisfactory biomarker to indicate a poor prognosis of renal artery revascularization in a 2-kidney, 1-clip hypertensive rat model. However, it is perhaps not a good early biomarker for the early detection of renovascular hypertension.
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Affiliation(s)
- Liqiang Li
- Department of Vascular Surgery, Xuanwu Hospital and Institute of Vascular Surgery, Capital Medical University, Beijing, China
| | - Cong Wang
- Department of Vascular Surgery, Xuanwu Hospital and Institute of Vascular Surgery, Capital Medical University, Beijing, China
| | - Yongquan Gu
- Department of Vascular Surgery, Xuanwu Hospital and Institute of Vascular Surgery, Capital Medical University, Beijing, China
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Reverte V, Gogulamudi VR, Rosales CB, Musial DC, Gonsalez SR, Parra-Vitela AJ, Galeas-Pena M, Sure VN, Visniauskas B, Lindsey SH, Katakam PVG, Prieto MC. Urinary angiotensinogen increases in the absence of overt renal injury in high fat diet-induced type 2 diabetic mice. J Diabetes Complications 2020; 34:107448. [PMID: 31761419 PMCID: PMC6981045 DOI: 10.1016/j.jdiacomp.2019.107448] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/09/2019] [Accepted: 09/07/2019] [Indexed: 12/31/2022]
Abstract
AIM OF THE STUDY During type 2 diabetes (T2D) and hypertension there is stimulation of renal proximal tubule angiotensinogen (AGT), but whether urinary excretion of AGT (uAGT) is an indicator of glomerular damage or intrarenal RAS activation is unclear. We tested the hypothesis that elevations in uAGT can be detected in the absence of albuminuria in a mouse model of T2D. METHODS Male C57BL/6 mice (N = 10) were fed a high fat (HFD; 45% Kcal from fat) for 28 weeks, and the metabolic phenotype including body weight, blood pressures, glucose, insulin, ippGTT, HOMA-IR, and cholesterol was examined. In addition, kidney Ang II content and reactive oxygen species (ROS) was measured along with urinary albumin, creatinine, Ang II, and AGT. RESULTS All parameters consistent with T2D were present in mice after 12-14 weeks on the HFD. Systolic BP increased after 18 weeks in HFD but not NFD mice. Intrarenal ROS and Ang II concentrations were also increased in HFD mice. Remarkably, these changes paralleled the augmentation uAGT excretion (3.66 ± 0.50 vs. 0.92 ± 0.13 ng/mg by week 29; P < 0.01), which occurred in the absence of overt albuminuria. CONCLUSIONS In HFD-induced T2D mice, increases in uAGT occur in the absence of overt renal injury, indicating that this biomarker accurately detects early intrarenal RAS activation.
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Affiliation(s)
- Virginia Reverte
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA
| | | | - Carla B Rosales
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA
| | - Diego C Musial
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA; Department of Pharmacology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
| | - Sabrina R Gonsalez
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Michelle Galeas-Pena
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA
| | - Venkata N Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, USA
| | - Bruna Visniauskas
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA
| | - Sarah H Lindsey
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, USA
| | - Prasad V G Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, USA
| | - Minolfa C Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, USA; Hypertension and Renal Center of Excellence, New Orleans, USA.
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12
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Rodriguez R, Lee A, Mathis KW, Broome HJ, Thorwald M, Martinez B, Nakano D, Nishiyama A, Ryan MJ, Ortiz RM. Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats. Am J Physiol Renal Physiol 2018; 315:F1081-F1090. [PMID: 29993275 DOI: 10.1152/ajprenal.00156.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-α (TNF-α) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-α inhibitor + angiotensin receptor blocker (ETAN+ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN+ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN+ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation.
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Affiliation(s)
- Ruben Rodriguez
- Department of Molecular and Cellular Biology, University of California, Merced, California
| | - Andrew Lee
- Department of Molecular and Cellular Biology, University of California, Merced, California
| | - Keisa W Mathis
- Department of Physiology and Anatomy, University of North Texas Health Science Center , Fort Worth, Texas
| | - Hanna J Broome
- Department of Biological Sciences, Mississippi College , Clinton, Mississippi
| | - Max Thorwald
- Department of Molecular and Cellular Biology, University of California, Merced, California
| | - Bridget Martinez
- Department of Molecular and Cellular Biology, University of California, Merced, California.,School of Medicine, St. George's University , St. George's , Grenada.,Department of Physics and Engineering, Los Alamos National Laboratory , Los Alamos, New Mexico
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University , Takamatsu , Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University , Takamatsu , Japan
| | - Michael J Ryan
- Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, Mississippi.,G.V. (Sonny) Montgomery Veterans Affairs Medical Center , Jackson, Mississippi
| | - Rudy M Ortiz
- Department of Molecular and Cellular Biology, University of California, Merced, California
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13
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Nishiyama A, Kobori H. Independent regulation of renin-angiotensin-aldosterone system in the kidney. Clin Exp Nephrol 2018; 22:1231-1239. [PMID: 29600408 PMCID: PMC6163102 DOI: 10.1007/s10157-018-1567-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 03/21/2018] [Indexed: 01/13/2023]
Abstract
Renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating renal hemodynamics and functions, as well as in the pathophysiology of hypertension and renal disease. In the kidney, angiotensin II (Ang II) production is controlled by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid with much higher concentrations than those existing in the circulation. Inappropriate activation of the intrarenal RAAS is an important contributor to the pathogenesis of hypertension and renal injury. It has been revealed that intrarenal Ang II levels are predominantly regulated by angiotensinogen and therefore, urinary angiotensinogen could be a biomarker for intrarenal Ang II generation. In addition, recent studies have demonstrated that aldosterone contributes to the progression of renal injury via direct actions on glomerular podocytes, mesangial cells, proximal tubular cells and tubulo-interstitial fibroblasts through the activation of locally expressed mineralocorticoid receptor. Thus, it now appears that intrarenal RAAS is independently regulated and its inappropriate activation contributes to the pathogenesis of the development of hypertension and renal disease. This short review article will focus on the independent regulation of the intrarenal RAAS with an emphasis on the specific role of angiotensinogen.
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Affiliation(s)
- Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1 Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
| | - Hiroyuki Kobori
- Departments of Pharmacology and Nephrology, Faculty of Medicine, International University of Health and Welfare, Narita, Japan
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14
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Mito-TEMPO Alleviates Renal Fibrosis by Reducing Inflammation, Mitochondrial Dysfunction, and Endoplasmic Reticulum Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5828120. [PMID: 29765500 PMCID: PMC5889907 DOI: 10.1155/2018/5828120] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/01/2018] [Accepted: 01/15/2018] [Indexed: 12/14/2022]
Abstract
Background Renal fibrosis is a common pathological symptom of chronic kidney disease (CKD). Many studies support that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are implicated in the pathogenesis of CKD. In our study, we investigated the benefits and underlying mechanisms of Mito-TEMPO on renal fibrosis in 5/6 nephrectomy mice. Methods Mice were randomly divided into five groups as follows: control group, CKD group, CKD + Mito-TEMPO (1 mg·kg-1·day-1) group, CKD + Mito-TEMPO (3 mg·kg-1·day-1) group, and Mito-TEMPO group (3 mg·kg-1·day-1). Renal fibrosis was evaluated by PAS, Masson staining, immunohistochemistry, and real-time PCR. Oxidative stress markers such as SOD2 activity and MDA level in serum and isolated mitochondria from renal tissue were measured by assay kits. Mitochondrial superoxide production was evaluated by MitoSOX staining and Western blot. Mitochondrial dysfunction was assessed by electron microscopy and real-time PCR. ER stress-associated protein was measured by Western blot. Results Impaired renal function and renal fibrosis were significantly improved by Mito-TEMPO treatment. Furthermore, inflammation cytokines, profibrotic factors, oxidative stress markers, mitochondrial dysfunction, and ER stress were all increased in the CKD group. However, these effects were significantly ameliorated in the Mito-TEMPO treatment group. Conclusions Mito-TEMPO ameliorates renal fibrosis by alleviating mitochondrial dysfunction and endoplasmic reticulum stress possibly through the Sirt3-SOD2 pathway, which sheds new light on prevention of renal fibrosis in chronic kidney disease.
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15
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Fakhruddin S, Alanazi WA, Alhamami HN, Briski KP, Jackson KE. Hyperglycaemia induced by chronic i.p. and oral glucose loading leads to hypertension through increased Na + retention in proximal tubule. Exp Physiol 2018; 103:236-249. [PMID: 29114945 DOI: 10.1113/ep086604] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 11/03/2017] [Indexed: 12/11/2022]
Abstract
NEW FINDINGS What is the central question of the study? Chronic glucose feeding accompanied by glucose injection (i.p.) causes sustained hyperglycaemia and hypertension in rats. The exact reason for the hypertension is not known. We explore some molecular pathways of the renal proximal tubule that might promote Na+ retention. What is the main finding and its importance? Development of hypertension was mediated by upregulation of the renal renin-angiotensin system and oxidative stress, acting via the Na+ -K+ -ATPase α1 -subunit in the proximal tubule, which appears to pump intracellular Na+ into the extracellular space, increasing Na+ reabsorption and blood pressure. Targeting the Na+ -K+ -ATPase α1 -subunit might provide a therapeutic strategy for treatment of hypertension. Feeding animals glucose-, fructose-, sucrose- and fat-enriched diets can lead to diet-induced hyperglycaemia, the severity of which largely depends on the types and concentrations of the nutrients used and duration of the dietary intervention. As a dietary intervention strategy, we adopted glucose-enriched diet and drinking water, with i.p. glucose injection at a dose previously determined to be effective to establish a sustained hyperglycaemia over a period of 2 weeks. We used four groups of Sprague-Dawley rats: control; glucose treated; glucose plus tempol treated; and glucose plus captopril treated. Blood glucose concentrations started to increase gradually from day 3, peaked (321 mg dl-1 ) at day 12 and remained at similar levels until the end of the study on day 14 in the glucose treated-group compared with the control group. In contrast, the tempol- and captopril-treated groups showed significantly high glucose concentrations only in the second week. The plasma insulin concentration was significantly increased in glucose-treated animals but not in tempol- and captopril-treated groups when compared with the control rats. We also observed elevated blood pressure in the glucose-treated group compared with the control group, which can be attributed to the increase in angiotensin II concentrations from 46.67 to 99 pg ml-1 (control versus glucose), increased oxidative stress in the cortical proximal tubule (PT), decreased urine flow, and increased expression and activity of the PT-specific α1 -subunit of Na+ -K+ -ATPase in the renal cortex, which is responsible for increased sodium reabsorption from epithelial cells of PT into the peritubular capillaries, leading to increased blood volume and eventual blood pressure. All these events were reversed in captopril- and tempol-treated animals.
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Affiliation(s)
- Selim Fakhruddin
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Monroe, LA, USA
| | - Wael A Alanazi
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Monroe, LA, USA
| | - Hussain N Alhamami
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Monroe, LA, USA
| | - Karen P Briski
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Monroe, LA, USA
| | - Keith E Jackson
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Monroe, LA, USA
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16
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Wang J, Shibayama Y, Kobori H, Liu Y, Kobara H, Masaki T, Wang Z, Nishiyama A. High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5. PLoS One 2017; 12:e0185600. [PMID: 29053707 PMCID: PMC5650141 DOI: 10.1371/journal.pone.0185600] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 09/17/2017] [Indexed: 01/01/2023] Open
Abstract
High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5’-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy.
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Affiliation(s)
- Juan Wang
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Yuki Shibayama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hiroyuki Kobori
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Departments of Pharmacology and of Nephrology, School of Medicine, International University of Health and Welfare, Tokyo, Japan
| | - Ya Liu
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Zhiyu Wang
- Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- * E-mail:
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17
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Mizushige T, Kobori H, Hitomi H, Nishijima Y, Tomoda F, Morimoto S, Kohno M, Nishiyama A. Urinary Angiotensinogen Could Be a Prognostic Marker of the Renoprotection of Olmesartan in Metabolic Syndrome Patients. Int J Mol Sci 2016; 17:E1800. [PMID: 27801805 PMCID: PMC5133801 DOI: 10.3390/ijms17111800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 01/07/2023] Open
Abstract
This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients (eight women, 57.88 ± 2.00 years), 5-40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen (normalized by urinary concentrations of creatinine) and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly (p < 0.05). Based on the % change in urinary albumin, patients were divided into two groups, responders (<-50%) and non-responders (≥-50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index (0.500, specificity: 11/12 = 91.7% and sensitivity: 7/12 = 58.3%) was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment (Group H, n = 16) and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.
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Affiliation(s)
- Tomoko Mizushige
- Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
| | - Hiroyuki Kobori
- Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
- Departments of Pharmacology and of Nephrology, School of Medicine, International University of Health and Welfare, Tokyo 107-0062, Japan.
- Departments of Physiology and of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Hirofumi Hitomi
- Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
| | - Yoko Nishijima
- Department of Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
| | - Fumihiro Tomoda
- The Second Department of Internal Medicine, Toyama University School of Medicine, Toyama 930-0194, Japan.
| | - Satoshi Morimoto
- The Second Department of Internal Medicine, Kansai Medical University, Osaka 573-1010, Japan.
| | - Masakazu Kohno
- Department of Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
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18
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Minas JN, Thorwald MA, Conte D, Vázquez-Medina JP, Nishiyama A, Ortiz RM. Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats. Clin Exp Pharmacol Physiol 2016; 42:1178-88. [PMID: 26234762 DOI: 10.1111/1440-1681.12473] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 06/30/2015] [Accepted: 06/30/2015] [Indexed: 11/30/2022]
Abstract
Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension.
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Affiliation(s)
- Jacqueline N Minas
- Molecular Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
| | - Max A Thorwald
- Molecular Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
| | - Debra Conte
- Molecular Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
| | | | - Akira Nishiyama
- Department of Pharmacology, Kagawa Medical University, Kagawa, Japan
| | - Rudy M Ortiz
- Molecular Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
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19
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Tojo A, Kinugasa S, Fujita T, Wilcox CS. A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats. Diabetes Metab Syndr Obes 2016; 9:1-10. [PMID: 26848273 PMCID: PMC4723098 DOI: 10.2147/dmso.s91245] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The mechanism of activation of local renal renin-angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 μg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen.
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Affiliation(s)
- Akihiro Tojo
- Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
- Correspondence: Akihiro Tojo, Division of Nephrology and Endocrinology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, Tel +81 3 3815 5411 ext 37219, Fax +81 3 3814 0021, Email
| | - Satoshi Kinugasa
- Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Toshiro Fujita
- Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Christopher S Wilcox
- Division of Nephrology and Hypertension, Center for Hypertension, Kidney and Vascular Research, Georgetown University, Washington, DC, USA
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20
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Nozako M, Koyama T, Nagano C, Sato M, Matsumoto S, Mitani K, Yasufuku R, Kohashi M, Yoshikawa T. An Atherogenic Paigen-Diet Aggravates Nephropathy in Type 2 Diabetic OLETF Rats. PLoS One 2015; 10:e0143979. [PMID: 26606054 PMCID: PMC4659596 DOI: 10.1371/journal.pone.0143979] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 11/11/2015] [Indexed: 11/18/2022] Open
Abstract
Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD) on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-α and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment.
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Affiliation(s)
- Masanori Nozako
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Takashi Koyama
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Chifumi Nagano
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Makoto Sato
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Satoshi Matsumoto
- Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Kiminobu Mitani
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Reiko Yasufuku
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Masayuki Kohashi
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
| | - Tomohiro Yoshikawa
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Tokushima, Japan
- * E-mail:
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21
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Zhuang Z, Bai Q, A L, Liang Y, Zheng D, Wang Y. Increased urinary angiotensinogen precedes the onset of albuminuria in normotensive type 2 diabetic patients. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:11464-11469. [PMID: 26617876 PMCID: PMC4637692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 07/26/2015] [Indexed: 06/05/2023]
Abstract
It was previously reported that intrarenal renin angiotensin system (RAS) plays a pivotal role in the onset and progression of diabetic nephropathy (DN). Urinary angiotensinogen (UAGT) was employed as a special index of the intrarenal RAS status and enhanced significantly at a very early stage of chronic kidney disease and type 1 diabetes. On the basis of these findings, the present study was performed to test the hypothesis that UAGT levels are increase even before the development of DN in type 2 diabetic patients without hypertension. 102 patients with type 2 diabetes mellitus (T2DM) and 18 healthy volunteers were studied cross-sectionally. Clinical data were collected and morning spot urine samples were obtained from all participants. UAGT levels were detected by an enzyme-linked immunosorbent assay (ELISA). As a result, UAGT to creatinine ratio (UAGT/Cr) was significantly enhanced in T2DM patients before the appearance of urinary albumin (UALB) and further increased to a greater degree in albuminuric patients. UAGT/Cr levels were positively correlated with Log (UALB to creatinine ratio) and diastolic blood pressure, but negatively correlated with estimated glomerular filtration rate. These data indicate that elevated UAGT levels precede the onset of albuminuria in normotensive T2DM patients. UAGT might potentially serve as an early marker to determine intrarenal RAS activity and predict progressive kidney disease in T2DM patients without hypertension.
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Affiliation(s)
- Zhen Zhuang
- Department of Nephrology, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua UniversityBeijing, China
| | - Qiong Bai
- The No. 3 Hospital of Peking UniversityBeijing, China
| | - Lata A
- The No. 3 Hospital of Peking UniversityBeijing, China
| | - Yaoxian Liang
- The People’s Hospital of Peking UniversityBeijing, China
| | - Danxia Zheng
- The No. 3 Hospital of Peking UniversityBeijing, China
| | - Yue Wang
- The No. 3 Hospital of Peking UniversityBeijing, China
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22
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Park Y, Kim H, Park L, Min D, Park J, Choi S, Park MH. Effective Delivery of Endogenous Antioxidants Ameliorates Diabetic Nephropathy. PLoS One 2015; 10:e0130815. [PMID: 26114547 PMCID: PMC4483240 DOI: 10.1371/journal.pone.0130815] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 05/26/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is thought to be partially due to the injury of renal cells and the renal micro-environment by free radicals. Free radial scavenging agents that inhibit free radical damage may well prevent the development of underlying conditions such as mesangial expansion (by inhibiting extracellular matrix expression) in these patients. METHODS Using techniques for intra-cellular delivery of peptides, we made metallothionein (MT) and superoxide dismutase (SOD), potent endogenous antioxidants, readily transducible into cell membrane and tested their protective effect against the development of DN in OLETF rats. Herein, we study antioxidant peptides for their ability to prevent oxidative damage to primary rat mesangial cells (MCs), which are important constituents of renal glomeruli. RESULTS Intraperitoneal administration of these antioxidants resulted in delivery to the kidney and decreased ROS and the expression of downstream signals in renal cells and postponed the usual progression to DN. In in vitro experiments, MT and SOD were efficiently transferred to MCs, and the increased removal of ROS by MT and SOD was proportional to the degree of scavenging enzymes delivered. MT and SOD decreased three major oxidative injuries (hyperglycemia, AGE and ROS exposure) and also injuries directly mediated by angiotensin II in MCs while changing downstream signal transduction. CONCLUSIONS The protective effects of MT and SOD for the progression of DN in experimental animals may be associated with the scavenging of ROS by MT and SOD and correlated changes in signal transduction downstream. Concomitant administration of these antioxidant peptides may prove to be a new approach for the prevention and therapy of DN.
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Affiliation(s)
- Yongsoo Park
- Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seoul, Korea
- * E-mail:
| | - Hyunok Kim
- Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seoul, Korea
| | - Leejin Park
- Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seoul, Korea
| | - Dongsoo Min
- Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seoul, Korea
| | - Jinseu Park
- Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon, Korea
| | - Sooyoung Choi
- Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon, Korea
| | - Moon Hyang Park
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
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23
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Exogenous C-type natriuretic peptide infusion ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis in rats. J Transl Med 2015; 95:263-72. [PMID: 25437644 DOI: 10.1038/labinvest.2014.149] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 07/28/2014] [Accepted: 09/12/2014] [Indexed: 11/08/2022] Open
Abstract
Although many experimental therapeutic roles for C-type natriuretic peptide (CNP) have been documented in the field of cardiovascular and pulmonary-vascular disease, the therapeutic uses of CNP to nephropathies are not as well documented. In this study, we established a rat model of unilateral ureteral obstruction (UUO) to observe the beneficial effects of CNP on tubulointerstitial fibrosis (TIF). In UUO rats, CNP administration induced a significant increase in plasma CNP levels, and caused a significant decrease in blood urea nitrogen and creatinine levels. In addition, CNP infusion also alleviated the pathological lesions and collagen IV accumulation in the obstructed kidneys through downregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression. In conclusion, exogenous CNP infusion can ameliorate UUO-induced TIF in rats. However, the use of CNP as a therapeutic agent requires further evaluation before being considered for human TIF.
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Okabe M, Miyazaki Y, Niimura F, Pastan I, Nishiyama A, Yokoo T, Ichikawa I, Matsusaka T. Unilateral ureteral obstruction attenuates intrarenal angiotensin II generation induced by podocyte injury. Am J Physiol Renal Physiol 2015; 308:F932-7. [PMID: 25673808 DOI: 10.1152/ajprenal.00444.2014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 02/06/2015] [Indexed: 01/13/2023] Open
Abstract
The renal tissue renin-angiotensin system is activated in chronic kidney diseases. We previously demonstrated that intrarenal ANG II is synthesized primarily from liver-derived angiotensinogen filtered through the glomerulus and that podocyte injury increases the passage of angiotensinogen into the tubular lumen and generation of ANG II. In the present study, we tested the effect of cessation of glomerular filtration by ureteral obstruction on renal ANG II generation in kidneys with podocyte injury under two experimental conditions. Ureteral obstruction is known to activate the renin-angiotensin system in nonproteinuric kidneys. Transgenic mice expressing hCD25 in podocyte (NEP25) were injected with 1.25 or 10 ng/g body wt of LMB2, a hCD25-targeted immunotoxin, subjected to unilateral ureteral ligation on the following day, and euthanized 7 and 4 days later, respectively. In both experiments, compared with the kidney in untreated wild-type mice, renal angiotensinogen protein, as assessed by immunostaining and Western blot analysis, was increased in the contralateral unobstructed kidney. However, it was markedly decreased in the obstructed kidney. Whereas intrarenal ANG II content was increased in the contralateral kidney compared with the untreated kidney (248 ± 83 vs. 106 ± 21 and 298 ± 185 vs. 64.8 ± 20 fmol/g kidney, respectively), this increase was suppressed in the obstructed kidney (161 ± 75 and 113 ± 34 fmol/g kidney, respectively), a pattern opposite to what we expected in obstructed kidneys without podocyte injury. Thus, our study indicates that the major source of increased renal ANG II in podocyte injury is filtered angiotensinogen.
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Affiliation(s)
- Masahiro Okabe
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Yoichi Miyazaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Fumio Niimura
- Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan; and
| | - Ira Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University School of Medicine, Kagawa, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Iekuni Ichikawa
- Tokai University School of Medicine, Kanagawa, Japan; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Taiji Matsusaka
- Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; Institute of Medical Science,
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25
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Mizushige T, Kobori H, Nishijima Y, Yano Y, Sakata K, Hayakawa M, Nishiyama A. Urinary Angiotensinogen Could Be a Prognostic Marker of Renoprotective Effects of Alogliptin in Patients with Type 2 Diabetes. J Diabetes Res 2015; 2015:517472. [PMID: 26380312 PMCID: PMC4562181 DOI: 10.1155/2015/517472] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/01/2015] [Accepted: 02/09/2015] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The aims of this study were (1) to examine the renoprotective effects of alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of alogliptin in patients with type 2 diabetes (T2D). METHODS In 43 patients with T2D (18 women, 66.1 ± 1.71 years), 25 mg/day of alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week alogliptin treatment. RESULTS Alogliptin treatment tended to decrease UAlbCR (99.6 ± 26.8 versus 114.6 ± 36.0 mg/g Cr, P = 0.198). Based on % change in UAlbCR, patients were divided into two groups, responders (< -25%) and nonresponders (≥ -25%), and a logistic analysis of UAGTCR before treatment showed cutoff value of 20.8 µg/g Cr. When all patients were redivided into two groups, those with higher values of UAGTCR before the treatment (Group H, n = 20) and those with lower values (Group L), Group H showed significantly decreased UAlbCR in response to alogliptin (-14.6 ± 8.6 versus +22.8 ± 16.8%, P = 0.033). CONCLUSION Urinary AGT could be a prognostic marker of renoprotective effects of alogliptin in patients with T2D.
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Affiliation(s)
- Tomoko Mizushige
- Kagawa University School of Medicine, Kagawa 761-0793, Japan
- Jichi Medical University School of Medicine, Tochigi, Japan
| | - Hiroyuki Kobori
- Kagawa University School of Medicine, Kagawa 761-0793, Japan
- Tulane University Health Sciences Center, New Orleans, LA, USA
- *Hiroyuki Kobori:
| | - Yoko Nishijima
- Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Yuichiro Yano
- Jichi Medical University School of Medicine, Tochigi, Japan
| | - Koji Sakata
- Miyazaki University School of Medicine, Miyazaki, Japan
| | | | - Akira Nishiyama
- Kagawa University School of Medicine, Kagawa 761-0793, Japan
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26
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Nishijima Y, Kobori H, Kaifu K, Mizushige T, Hara T, Nishiyama A, Kohno M. Circadian rhythm of plasma and urinary angiotensinogen in healthy volunteers and in patients with chronic kidney disease. J Renin Angiotensin Aldosterone Syst 2014; 15:505-8. [PMID: 25381307 PMCID: PMC4268126 DOI: 10.1177/1470320314557584] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the intrarenal activity of the renin-angiotensin system. Little is known about the circadian rhythm of AGT levels in plasma or urine. In this short article, making use of data in plasma and urine of healthy volunteers and patients with chronic kidney diseases, we first report that we were unable to find evidence for a circadian rhythm of AGT under any condition. Next we critically discuss to what degree elevated urinary AGT levels might be considered an independent biomarker that is not simply the non-specific consequence of proteinuria.
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Affiliation(s)
- Yoko Nishijima
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Japan
| | - Hiroyuki Kobori
- Department of Pharmacology, Kagawa University Faculty of Medicine, Japan
| | - Kumiko Kaifu
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Japan
| | - Tomoko Mizushige
- Department of Pharmacology, Kagawa University Faculty of Medicine, Japan
| | - Taiga Hara
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Faculty of Medicine, Japan
| | - Masakazu Kohno
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Japan
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Menne J, Ritz E, Ruilope LM, Chatzikyrkou C, Viberti G, Haller H. The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) observational follow-up study: benefits of RAS blockade with olmesartan treatment are sustained after study discontinuation. J Am Heart Assoc 2014; 3:e000810. [PMID: 24772521 PMCID: PMC4187490 DOI: 10.1161/jaha.114.000810] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that 40 mg Olmesartan medoxomil (OM) versus placebo delayed microalbuminuria onset in patients with type 2 diabetes and normoalbuminuria. Methods and Results One thousand seven hundred and fifty‐eight ROADMAP patients (placebo arm: 877; OM arm: 881) participated in the observational follow up (OFU) with an average of 3.3 years. They received standard medical care and micro‐ and macrovascular events were documented. During observational follow‐up 62.9% and 60.1% in the former OM and placebo group, respectively, received treatment with a RAS blocking agent. During the OFU period the systolic blood pressure (SBP) increased to mean values of 135 mm Hg in both groups. Patients who had developed microalbuminuria during ROADMAP had a higher incidence of cardio‐ and cerebrovascular events (OR 1.77, CI 1.03 to 3.03, P=0.039) during the OFU period compared with patients in whom this was not the case. Diabetic retinopathy was significantly reduced in the former OM group (8 [0.9%] versus 23 [2.6%], OR: 0.34, CI 0.15 to 0.78, P=0.011) and the rate of microalbuminuria was numerically reduced. Congestive heart failure requiring hospitalization (3 [0.3%] versus 12 [1.4%], OR: 0.23, CI 0.06 to 0.85, P=0.027) was reduced and there was a trend of reduced cardio‐/cerebrovascular events (OM versus Pb: 73 [8.3%] versus 86 [9.8%] patients). Seven (0.8%) deaths (including 2 CV events) were reported in former placebo patients versus 3 (0.3%) (non‐CV events) in former OM patients. Conclusions Development of microalbuminuria is a valid marker for future CV events. RAS blockade with Olmesartan might cause sustained reduction (legacy effect) of micro‐ and macrovascular events.
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Affiliation(s)
- Jan Menne
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany (J.M., C.C., H.H.)
| | - Eberhard Ritz
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany (E.R.)
| | - Luis M. Ruilope
- Division of Hypertension, Hospital 12 de Octubre, Madrid, Spain (L.M.R.)
| | - Christos Chatzikyrkou
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany (J.M., C.C., H.H.)
| | - Giancarlo Viberti
- King's College London School of Medicine, Guy's Hospital, London, UK (G.V.)
| | - Hermann Haller
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany (J.M., C.C., H.H.)
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Kamiyama M, Garner MK, Farragut KM, Sofue T, Hara T, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, Kobori H. Detailed localization of augmented angiotensinogen mRNA and protein in proximal tubule segments of diabetic kidneys in rats and humans. Int J Biol Sci 2014; 10:530-42. [PMID: 24910532 PMCID: PMC4046880 DOI: 10.7150/ijbs.8450] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Accepted: 04/22/2014] [Indexed: 01/13/2023] Open
Abstract
In the intrarenal renin-angiotensin system, angiotensinogen levels are well known to be increased in diabetes, and these enhanced intrarenal angiotensinogen levels may initiate the development and accelerate the progression of diabetic nephropathy. However, the specific localization of the augmented angiotensinogen in proximal tubule segments in diabetes is still unknown. We investigated the detailed localization of angiotensinogen in 3 proximal tubule segments in the diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. We also prepared OLETF rats treated with angiotensin II type 1 receptor blocker, olmesartan or with a combination of vasodilator agents. Moreover, biopsied samples of human kidney cortex were used to confirm the results of animal studies. We examined the co-localization of angiotensinogen with segment-specific markers by double staining using fluorescence in situ hybridization and/or immunofluorescence. Angiotensinogen mRNA expression was barely detectable in segment 1. In segment 3, the area of angiotensinogen mRNA expression was augmented in the OLETF rats compared with the LETO rats. Angiotensinogen protein expression areas in segments 1 and 3 were also increased in the OLETF rats compared with the LETO rats. Chronic treatment with olmesartan ameliorated these areas of augmented angiotensinogen expression. Biopsied human kidney samples showed similar results. These data suggest that the augmented angiotensinogen mRNA levels in segment 3 and angiotensinogen protein levels in segments 1 and 3 may contribute to the progression of diabetic nephropathy.
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Affiliation(s)
- Masumi Kamiyama
- 1. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 2. Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
| | - Michelle K Garner
- 1. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 2. Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
| | - Kristina M Farragut
- 1. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 2. Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
| | - Tadashi Sofue
- 4. Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Taiga Hara
- 4. Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Takashi Morikawa
- 6. Department of Nephrology and Hypertension, Osaka City General Hospital, Osaka 534-0021, Japan
| | - Yoshio Konishi
- 6. Department of Nephrology and Hypertension, Osaka City General Hospital, Osaka 534-0021, Japan
| | - Masahito Imanishi
- 6. Department of Nephrology and Hypertension, Osaka City General Hospital, Osaka 534-0021, Japan
| | - Akira Nishiyama
- 5. Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Hiroyuki Kobori
- 1. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 2. Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 3. Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 5. Department of Pharmacology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
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Angiotensin II reduces transport-dependent oxygen consumption but increases transport-independent oxygen consumption in immortalized mouse proximal tubular cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 812:157-163. [PMID: 24729228 DOI: 10.1007/978-1-4939-0620-8_21] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO₂). We investigated the effect of Ang II on QO₂ in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H₂O₂ for 48 h. QO₂ was determined during baseline (113 mmol/l NaCl; transport-dependent QO₂) and during sodium-free conditions (transport-independent QO₂). Ang II reduced transport-dependent QO₂ in wild-types, but not in p22(phox) which also displayed increased QO₂ at baseline. Transport-independent QO₂ was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO₂ in wild-type. Addition of H₂O₂ reduced transport-dependent QO₂ in wild-types, but not in p22(phox). Transport-independent QO₂ was unaffected by H₂O₂. The similar effects of Ang II and H₂O₂ to reduce transport-dependent QO₂ suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO₂ was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO₂ was not replicated by H₂O₂, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO₂ in proximal tubular cells and may be an important pathway modulating renal QO₂.
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30
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Soltysiak J, Skowronska B, Fichna P, Ostalska-Nowicka D, Stankiewicz W, Lewandowska-Stachowiak M, Lipkowska K, Zachwieja J. Urinary angiotensinogen and urinary sodium are associated with blood pressure in normoalbuminuric children with diabetes. Pediatr Nephrol 2014; 29:2373-8. [PMID: 24880819 PMCID: PMC4212134 DOI: 10.1007/s00467-014-2861-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 05/02/2014] [Accepted: 05/14/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of this study was to evaluate the association between blood pressure (BP) and urinary angiotensinogen excretion (uAGT) and renal sodium excretion (uNa) in children with type 1 diabetes mellitus (DM1). METHODS The study group consisted of 52 children with DM1 (28 males and 24 females) with albumin/creatinine ratio (ACR) below 30 mg/g and glomerular filtration rate (eGFR) above 90 ml/min/1.73 m(2). BP was assessed by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS The patients showed significantly increased uAGT values with respect to controls (median 0.00 and range 1.76 vs. 0.00 and 0.00 ng/mg, respectively). The significant increase of uAGT was observed even in prehypertensive patients. uAGT concentrations showed positive correlation with systolic and diastolic 24-h BP and with mean arterial pressure (MAP) (r = 0.594). uNa values were negatively correlated with BP parameters, uAGT, ACR and eGFR. CONCLUSIONS An increase in uAGT precedes hypertension (HTN) in normoalbuminuric children with DM1 and may be considered as a new marker of HTN. Decreased sodium excretion seems to be involved in the development of HTN and early renal injury. Both uAGT and uNa are associated with BP in normoalbuminuric diabetic children.
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Affiliation(s)
- Jolanta Soltysiak
- Department of Pediatric Cardiology and Nephrology, Poznan University of Medical Sciences, 27/33 Szpitalna St., 60-572, Poznan, Poland,
| | - Bogda Skowronska
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Fichna
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - Danuta Ostalska-Nowicka
- Department of Pediatric Cardiology and Nephrology, Poznan University of Medical Sciences, 27/33 Szpitalna St., 60-572 Poznan, Poland
| | - Witold Stankiewicz
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - Maria Lewandowska-Stachowiak
- Department of Pediatric Cardiology and Nephrology, Poznan University of Medical Sciences, 27/33 Szpitalna St., 60-572 Poznan, Poland
| | - Katarzyna Lipkowska
- Department of Pediatric Cardiology and Nephrology, Poznan University of Medical Sciences, 27/33 Szpitalna St., 60-572 Poznan, Poland
| | - Jacek Zachwieja
- Department of Pediatric Cardiology and Nephrology, Poznan University of Medical Sciences, 27/33 Szpitalna St., 60-572 Poznan, Poland
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Kobori H, Kamiyama M, Harrison-Bernard LM, Navar LG. Cardinal role of the intrarenal renin-angiotensin system in the pathogenesis of diabetic nephropathy. J Investig Med 2013. [PMID: 23266706 DOI: 10.231/jim.0b013e31827c28bb] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of renin-angiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy (DN) is discussed with a focus on 4 themes: (1) introduction to RAS cascade, (2) intrarenal RAS in diabetes, (3) clinical outcomes of RAS blockade in DN, and (4) potential of urinary angiotensinogen as an early biomarker of intrarenal RAS status in DN. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of DN and that urinary angiotensinogen levels provide an index of intrarenal RAS activity.
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Affiliation(s)
- Hiroyuki Kobori
- Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA, USA.
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32
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Long-term hemodynamic and molecular effects persist after discontinued renin–angiotensin system blockade in patients with type 1 diabetes mellitus. Kidney Int 2013; 84:1246-53. [DOI: 10.1038/ki.2013.221] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 04/19/2013] [Accepted: 04/25/2013] [Indexed: 01/30/2023]
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Kamiyama M, Urushihara M, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, Kobori H. Oxidative stress/angiotensinogen/renin-angiotensin system axis in patients with diabetic nephropathy. Int J Mol Sci 2013; 14:23045-62. [PMID: 24284398 PMCID: PMC3856105 DOI: 10.3390/ijms141123045] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 11/07/2013] [Accepted: 11/07/2013] [Indexed: 01/22/2023] Open
Abstract
Although recent studies have proven that renin-angiotensin system (RAS) blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS) are important for intrarenal angiotensinogen (AGT) augmentation in the progression of diabetic nephropathy. However, no direct evidence is available to demonstrate that AGT expression is enhanced in the kidneys of patients with diabetes. To examine whether the expression levels of ROS- and RAS-related factors in kidneys are increased with the progression of diabetic nephropathy, biopsied samples from 8 controls and 27 patients with type 2 diabetes were used. After the biopsy, these patients were diagnosed with minor glomerular abnormality or diabetes mellitus by clinical and pathological findings. The intensities of AGT, angiotensin II (Ang II), 4-hydroxy-2-nonenal (4-HNE), and heme oxygenase-1 (HO-1) were examined by fluorescence in situ hybridization and/or immunohistochemistry. Expression levels were greater in patients with diabetes than in control subjects. Moreover, the augmented intrarenal AGT mRNA expression paralleled renal dysfunction in patients with diabetes. These data suggest the importance of the activated oxidative stress/AGT/RAS axis in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
- Masumi Kamiyama
- Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA; E-Mails: (M.K.); (M.U.)
- Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Maki Urushihara
- Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA; E-Mails: (M.K.); (M.U.)
- Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Takashi Morikawa
- Department of Nephrology and Hypertension, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka 534-0021, Japan; E-Mails: (T.M.); (Y.K.); (M.I.)
| | - Yoshio Konishi
- Department of Nephrology and Hypertension, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka 534-0021, Japan; E-Mails: (T.M.); (Y.K.); (M.I.)
| | - Masahito Imanishi
- Department of Nephrology and Hypertension, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka 534-0021, Japan; E-Mails: (T.M.); (Y.K.); (M.I.)
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Medical School, Miki, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan; E-Mail:
| | - Hiroyuki Kobori
- Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA; E-Mails: (M.K.); (M.U.)
- Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
- Department of Pharmacology, Kagawa University Medical School, Miki, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan; E-Mail:
- Department of Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-504-988-2591; Fax: +1-504-988-0911
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Kobori H, Mori H, Masaki T, Nishiyama A. Angiotensin II blockade and renal protection. Curr Pharm Des 2013; 19:3033-42. [PMID: 23176216 DOI: 10.2174/1381612811319170009] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 11/20/2012] [Indexed: 12/15/2022]
Abstract
Current national guidelines have recommended the use of renin-angiotensin system inhibitors, including angiotensin II type 1 receptor blockers (ARBs), in preference to other antihypertensive agents for treating hypertensive patients with chronic kidney disease. However, the mechanisms underlying the renoprotective effects of ARBs are multiple and complex. Blood pressure reduction by systemic vasodilation with an ARB contributes to its beneficial effects in treating kidney disease. Furthermore, ARB-induced renal vasodilation results in an increase in renal blood flow, leading to improvement of renal ischemia and hypoxia. ARBs are also effective in reducing urinary albumin excretion through a reduction in intraglomerular pressure and the protection of glomerular endothelium and/or podocyte injuries. In addition to blocking angiotensin II-induced renal cell and tissue injuries, ARBs can decrease intrarenal angiotensin II levels by reducing proximal tubular angiotensinogen and production of collecting duct renin, as well as angiotensin II accumulation in the kidney. In this review, we will briefly summarize our current understanding of the pharmacological effects of an ARB in the kidney. We will also discuss the possible mechanisms responsible for the renoprotective effects of ARBs on type 2 diabetic nephropathy.
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Affiliation(s)
- Hiroyuki Kobori
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Ikenobe 1750-1, Miki, Kita, Kagawa 761-0793, Japan
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Liang J, Tian S, Han J, Xiong P. Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction. Ren Fail 2013; 36:285-91. [DOI: 10.3109/0886022x.2013.844644] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Gorin Y, Block K. Nox4 and diabetic nephropathy: with a friend like this, who needs enemies? Free Radic Biol Med 2013; 61:130-42. [PMID: 23528476 PMCID: PMC3716866 DOI: 10.1016/j.freeradbiomed.2013.03.014] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 03/12/2013] [Accepted: 03/16/2013] [Indexed: 12/19/2022]
Abstract
Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, a complication of diabetes in the kidney. NADPH oxidases of the Nox family are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current understanding of the roles of Nox catalytic and regulatory subunits in the processes that control mesangial cell, podocyte, and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-β. The role of the Nox isoform Nox4 in the redox processes that alter renal biology in diabetes is highlighted.
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Affiliation(s)
- Yves Gorin
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
| | - Karen Block
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; Audie L. Murphy Memorial Hospital Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
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37
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Abstract
Oxidative stress has been linked to the pathogenesis of the major complications of diabetes in the kidney, the heart, the eye or the vasculature. NADPH oxidases of the Nox family are a major source of ROS (reactive oxygen species) and are critical mediators of redox signalling in cells from different organs afflicted by the diabetic milieu. In the present review, we provide an overview of the current knowledge related to the understanding of the role of Nox in the processes that control cell injury induced by hyperglycaemia and other predominant factors enhanced in diabetes, including the renin–angiotensin system, TGF-β (transforming growth factor-β) and AGEs (advanced glycation end-products). These observations support a critical role for Nox homologues in diabetic complications and indicate that NADPH oxidases are an important therapeutic target. Therefore the design and development of small-molecule inhibitors that selectively block Nox oxidases appears to be a reasonable approach to prevent or retard the complications of diabetes in target organs. The bioefficacy of these agents in experimental animal models is also discussed in the present review.
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Fan YY, Kobori H, Nakano D, Hitomi H, Mori H, Masaki T, Sun YX, Zhi N, Zhang L, Huang W, Zhu B, Li P, Nishiyama A. Aberrant activation of the intrarenal renin-angiotensin system in the developing kidneys of type 2 diabetic rats. Horm Metab Res 2013; 45:338-43. [PMID: 23322513 PMCID: PMC3655199 DOI: 10.1055/s-0032-1331256] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
We have previously reported that intrarenal angiotensin II (Ang II) levels are increased long before diabetes becomes apparent in obese Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of type 2 diabetes. In this study, we examined the changes in intrarenal renin-angiotensin system (RAS) activity in the developing kidneys of OLETF rats. Ang II contents and mRNA levels of RAS components were measured in male OLETF and control Long-Evans Tokushima (LETO) rats at postnatal days (PND) 1, 5, and 15, and at 4-30 weeks of age. In both LETO and OLETF rats, kidney Ang II levels peaked at PND 1, then decreased during the pre- and post-weaning periods. However, Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), were not significantly different between LETO and OLETF rats. Intrarenal Ang IIcontents further decreased during puberty (from 7 to 11 weeks of age) in LETO rats, bur not in OLETF rats. At 11 weeks of age, kidney Ang II levels, urinary AGT excretion, and mRNA levels of AGT and renin were higher in OLETF rats than in LETO rats, while blood glucose levels were not significantly different between these groups of rats. These data indicate that continued intrarenal expression of Ang II during pubescence contributes to the increases in intrarenal Ang II levels in prediabetic OLETF rats, and is associated with increased intrarenal AGT and renin expression. Inappropriate activation of the intrarenal RAS in the prediabetic stage may facilitate the onset and development of diabetic nephropathy in later life.
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MESH Headings
- Albuminuria/complications
- Angiotensin II/metabolism
- Angiotensinogen/metabolism
- Animals
- Blood Glucose/metabolism
- Blood Pressure
- Body Weight
- Collagen/genetics
- Collagen/metabolism
- Connective Tissue Growth Factor/genetics
- Connective Tissue Growth Factor/metabolism
- Creatinine/urine
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/urine
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/urine
- Female
- Gene Expression Regulation
- Kidney/growth & development
- Kidney/metabolism
- Organ Size
- Peptidyl-Dipeptidase A/metabolism
- Rats
- Rats, Inbred OLETF
- Receptors, Angiotensin/metabolism
- Renin/metabolism
- Renin-Angiotensin System
- Time Factors
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism
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Affiliation(s)
- Y-Y Fan
- Department of Traditional Chinese Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China.
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Nishijima Y, Kobori H, Sofue T, Kaifu K, Moriwaki K, Hara T, Hitomi H, Kohno M, Nishiyama A. Important aspects of urine sampling for angiotensinogen measurement: time and preservation conditions in healthy individuals. TOHOKU J EXP MED 2013; 228:333-9. [PMID: 23132274 DOI: 10.1620/tjem.228.333] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Intrarenal renin-angiotensin system (RAS) plays an important role for the pathogenesis of renal injuries. Experimental studies have demonstrated that angiotensinogen levels in renal tissues reflect the activity of intrarenal RAS. However, dynamics of urinary angiotensinogen have not been investigated in detail. Therefore, we examined the preservation conditions of the measured values of urinary angiotensinogen concentrations and an ultradian rhythm of urinary angiotensinogen excretion in humans. Urine samples were collected from 24 healthy volunteers. The urinary concentrations of angiotensinogen were measured by using ELISA. Two different urine preservation conditions were examined. One cycle of freeze-and-thaw did not change the measured values of urinary angiotensinogen concentrations. Moreover, to keep urine samples at room temperature for 12 hours did not change the measured values of urinary angiotensinogen concentrations. Thus, preservation conditions do not change the measured values of urinary angiotensinogen concentrations. Regarding an ultradian rhythm, blood pressure and the urinary concentrations of angiotensinogen were measured at 09:00, 13:00, and 16:00. The averaged levels of blood pressure were similar over the time. The average of urinary angiotensinogen/creatinine (Cr) ratios was 8.73 ± 1.15 ng/mg Cr at 09:00, 9.53 ± 1.58 ng/mg Cr at 13:00, and 8.58 ± 1.26 ng/mg Cr at 16:00. The urinary angiotensinogen excretion in healthy volunteers does not have an ultradian change during the daytime (P = 0.482). This may be another indication that the intrarenal RAS is independent of the systemic RAS. We have to pay attention to these findings in handling urine samples for measurements of angiotensinogen.
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Affiliation(s)
- Yoko Nishijima
- Department of Cardio Renal and Cerebro Vascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Abstract
The most common cause of end stage renal disease (ESRD) requiring dialysis is diabetes. Both environmental and genetic factors have been postulated as the risk factors of Diabetic Nephropathy (DN). Hyperglycemia-induced metabolic and hemodynamic pathways are recognized to be mediators of kidney injury. Multiple biochemical pathways have been postulated that explain how hyperglycemia causes tissue damage: Non-enzymatic glycation that generates advanced glycation end products, activation of protein kinase C, acceleration of the polyol pathway and oxidative stress. Three major histologic pathological changes occur in DN: Mesangial expansion, GBM thickening, and glomerular sclerosis. It now seems clear in targeting a therapeutic regimen to achieve blood glucose, blood pressure and proteunuric goals, dietary protein and salt restriction, weight reduction, aggressive lipid lowering, smoking cessation and exercise. Multiple intensive interventions reduce cardiovascular events as well as nephropathy by about half when compared with conventional multifactorial treatment.
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Imanishi M, Okada N, Konishi Y, Morikawa T, Maeda I, Kitabayashi C, Masada M, Shirahashi N, Wilcox CS, Nishiyama A. Angiotensin II receptor blockade reduces salt sensitivity of blood pressure through restoration of renal nitric oxide synthesis in patients with diabetic nephropathy. J Renin Angiotensin Aldosterone Syst 2013; 14:67-73. [PMID: 22859713 DOI: 10.1177/1470320312454764] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION We have previously demonstrated the increased salt sensitivity of blood pressure (BP) in diabetic patients with early nephropathy. Here, we examined the effects of an angiotensin II receptor blocker (ARB) on salt sensitivity and renal oxidative stress or nitric oxide (NO) in those patients. PATIENTS AND METHODS Type 2 diabetic patients with (n = 6) and without (n = 6) microalbuminuria were studied on a high-salt diet for one week and on a salt-restricted diet for one week. The study was repeated in the patients with microalbuminuria during treatment with an ARB, valsartan (80 mg/day). Salt sensitivity was assessed from the BP/sodium excretion curve. Urinary excretion rates of NOx, 8-hydroxy-2-deoxyguanosine as a marker of oxidative stress, and plasma tetrahydrobiopterin as a cofactor for NO synthase were measured. RESULTS Compared with diabetic patients without microalbuminuria, patients with microalbuminuria showed greater salt sensitivity and lower urinary excretion of NOx. In the patients with microalbuminuria, treatment with valsartan reduced salt sensitivity in association with increased NOx excretion, reduced 8-hydroxy-2,-deoxyguanosine excretion, and increased plasma tetrahydrobiopterin levels. CONCLUSIONS These data support the hypothesis that ARBs reduce the salt sensitivity of BP by decreasing renal oxidative stress and restoring NO activity in diabetic patients with microalbuminuria.
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Affiliation(s)
- Masahito Imanishi
- Department of Nephrology and Hypertension, Osaka City General Hospital, Japan.
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Kobori H, Kamiyama M, Harrison-Bernard LM, Navar LG. Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy. J Investig Med 2013; 61:256-264. [DOI: 10.2310/jim.0b013e31827c28bb] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of renin-angiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy (DN) is discussed with a focus on 4 themes: (1) introduction to RAS cascade, (2) intrarenal RAS in diabetes, (3) clinical outcomes of RAS blockade in DN, and (4) potential of urinary angiotensinogen as an early biomarker of intrarenal RAS status in DN. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of DN and that urinary angiotensinogen levels provide an index of intrarenal RAS activity.
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Affiliation(s)
- Hiroyuki Kobori
- *Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center
| | - Masumi Kamiyama
- *Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center
| | | | - L. Gabriel Navar
- *Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center
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Kosaka S, Pelisch N, Rahman M, Nakano D, Hitomi H, Kobori H, Fukuoka N, Kobara H, Mori H, Masaki T, Cervenka L, Matsumura Y, Houchi H, Nishiyama A. Effects of Angiotensin II AT1^|^ndash;Receptor Blockade on High Fat Diet^|^ndash;Induced Vascular Oxidative Stress and Endothelial Dysfunction in Dahl Salt-Sensitive Rats. J Pharmacol Sci 2013; 121:95-102. [DOI: 10.1254/jphs.12169fp] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Abstract
Renal failure in type 2 diabetes has been termed "a medical catastrophe of worldwide dimension". In 2001, we found in our unit that 49% of incident patients requiring maintenance hemodialysis had diabetes (i.e. 98/million population/year), 6% of whom had type 1 and most (94%) had type 2 diabetes, i.e. more than the than reported frequency in Germany (approximately 35% of incident patients). The frequency is underestimated because hyperglycemia is often lost in the preterminal phase when diabetic patients lose weight and fasting hyperglycemia.
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MESH Headings
- Blood Pressure/drug effects
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/psychology
- Diabetes Mellitus, Type 1/therapy
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/psychology
- Diabetes Mellitus, Type 2/therapy
- Diabetic Nephropathies/diagnosis
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/physiopathology
- Diabetic Nephropathies/therapy
- Disease Progression
- Dyslipidemias/drug therapy
- Dyslipidemias/etiology
- Glomerular Filtration Rate/drug effects
- Humans
- Hyperglycemia/drug therapy
- Hyperglycemia/etiology
- Kidney/drug effects
- Kidney/pathology
- Kidney/physiopathology
- Kidney Failure, Chronic/etiology
- Kidney Failure, Chronic/physiopathology
- Kidney Failure, Chronic/prevention & control
- Medication Therapy Management
- Outcome Assessment, Health Care
- Proteinuria/etiology
- Proteinuria/physiopathology
- Renin-Angiotensin System/drug effects
- Risk Reduction Behavior
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Affiliation(s)
- Eberhard Ritz
- University of Heidelberg, Nierenzentrum, Im Neuenheimer Feld 162, Heidelberg 69120, Germany.
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Khurana S, Bruggeman LA, Kao HY. Nuclear hormone receptors in podocytes. Cell Biosci 2012; 2:33. [PMID: 22995171 PMCID: PMC3543367 DOI: 10.1186/2045-3701-2-33] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 08/10/2012] [Indexed: 11/14/2022] Open
Abstract
Nuclear receptors are a family of ligand-activated, DNA sequence-specific transcription factors that regulate various aspects of animal development, cell proliferation, differentiation, and homeostasis. The physiological roles of nuclear receptors and their ligands have been intensively studied in cancer and metabolic syndrome. However, their role in kidney diseases is still evolving, despite their ligands being used clinically to treat renal diseases for decades. This review will discuss the progress of our understanding of the role of nuclear receptors and their ligands in kidney physiology with emphasis on their roles in treating glomerular disorders and podocyte injury repair responses.
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Affiliation(s)
- Simran Khurana
- Department of Biochemistry, School of Medicine, Case Western Reserve University (CWRU) and the Comprehensive Cancer Center of CWRU, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
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Advanced glycation endproducts stimulate renal epithelial cells to release chemokines that recruit macrophages, leading to renal fibrosis. Biosci Biotechnol Biochem 2012; 76:1741-5. [PMID: 22972340 DOI: 10.1271/bbb.120347] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Diabetic nephropathy is a major complication of diabetes and tubulointerstitial fibrosis is one of its manifestations. This study aimed to clarify the pathogenicity of advanced glycation endproducts (AGEs) toward NRK-52E, a tubular epithelial cell line. The AGE-exposed cells significantly increased gene expression of transforming growth factor beta, plasminogen activator inhibitor-1, and tissue transglutaminase, and a medium conditioned by them showed strong potential to recruit macrophages, partly through a chemokine, monocyte chemoattractant protein-1. Albumin denatured by maintenance at 37 °C for 120 d exhibited similar activities, but they were lower than those of the AGEs. Thus, AGEs generated in diabetic patients might exacerbate fibrosis in the kidneys directly through renal epithelial cell stimulation, and indirectly by recruitment of macrophages.
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Kobori H, Urushihara M. Augmented intrarenal and urinary angiotensinogen in hypertension and chronic kidney disease. Pflugers Arch 2012; 465:3-12. [PMID: 22918624 DOI: 10.1007/s00424-012-1143-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 08/03/2012] [Accepted: 08/06/2012] [Indexed: 12/22/2022]
Abstract
Activated intrarenal renin-angiotensin system plays a cardinal role in the pathogenesis of hypertension and chronic kidney disease. Angiotensinogen is the only known substrate for renin, which is the rate-limiting enzyme of the renin-angiotensin system. Because the levels of angiotensinogen are close to the Michaelis-Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin-angiotensin system activity, and thus, upregulation of angiotensinogen leads to an increase in the angiotensin II levels and ultimately increases blood pressure. Recent studies using experimental animal models have documented the involvement of angiotensinogen in the intrarenal renin-angiotensin system activation and development of hypertension. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in experimental models of hypertension and chronic kidney disease, supporting the important roles of angiotensinogen in the development and the progression of hypertension and chronic kidney disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status in angiotensin II-infused rats. Also, a direct quantitative method has been developed recently to measure urinary angiotensinogen using human angiotensinogen enzyme-linked immunosorbent assay. These data prompted us to measure urinary angiotensinogen in patients with hypertension and chronic kidney disease, and investigate correlations with clinical parameters. This short article will focus on the role of the augmented intrarenal angiotensinogen in the pathophysiology of hypertension and chronic kidney disease. In addition, the potential of urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertension and chronic kidney disease will be also discussed.
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Affiliation(s)
- Hiroyuki Kobori
- Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, #SL39, New Orleans, LA 70112-2699, USA.
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Kamiyama M, Zsombok A, Kobori H. Urinary angiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetes. J Pharmacol Sci 2012; 119:314-23. [PMID: 22850612 DOI: 10.1254/jphs.12076fp] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Urinary excretion of albumin (UAlb) is used clinically as a marker of diabetic nephropathy (DN). Although DN was thought to be a unidirectional process, recent studies demonstrated that a large proportion of patients diagnosed with DN reverted to normoalbuminuria. Moreover, despite the normoalbuminuria, one-third of them exhibited reduced renal function even during the microalbuminuric stage. This study was performed to investigate whether urinary angiotensinogen (UAGT) level may serve as a useful marker of the early stage of experimental type 1 diabetes (T1DM). T1DM was induced by a single intraperitoneal injection of streptozotocin. Control mice were injected with citrate buffer. Two days after streptozotocin injection, half of the mice received continuous insulin treatment. Our data showed that UAlb excretion was increased 6 days after streptozotocin injection compared to controls, whereas UAGT excretion was increased at an earlier time point. These increases were reversed by insulin treatment. The UAGT to UAlb ratio was increased in diabetic mice compared to control mice. Furthermore, the increased AGT expression in the kidneys was observed in diabetic mice. These data suggest that UAGT might be useful as a novel early biomarker of activation of the renin-angiotensin system in experimental type 1 diabetes.
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Affiliation(s)
- Masumi Kamiyama
- Department of Physiology, Tulane University Health Sciences Center, USA
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Kitada K, Nakano D, Liu Y, Fujisawa Y, Hitomi H, Shibayama Y, Shibata H, Nagai Y, Mori H, Masaki T, Kobori H, Nishiyama A. Oxidative stress-induced glomerular mineralocorticoid receptor activation limits the benefit of salt reduction in Dahl salt-sensitive rats. PLoS One 2012; 7:e41896. [PMID: 22911865 PMCID: PMC3404044 DOI: 10.1371/journal.pone.0041896] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 06/27/2012] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Mineralocorticoid receptor (MR) antagonists attenuate renal injury in salt-sensitive hypertensive rats with low plasma aldosterone levels. We hypothesized that oxidative stress causes MR activation in high-salt-fed Dahl salt-sensitive rats. Furthermore, we determined if MR activation persisted and induced renal injury, even after switching from a high- to a normal-salt diet. METHODS AND FINDINGS High-salt feeding for 4 weeks increased dihydroethidium fluorescence (DHE, an oxidant production marker), p22phox (a NADPH oxidase subunit) and serum and glucocorticoid-regulated kinase-1 (SGK1, an MR transcript) in glomeruli, compared with normal-salt feeding, and these changes persisted 4 weeks after salt withdrawal. Tempol treatment (0.5 mmol/L) during high-salt feeding abolished the changes in DHE fluorescence, p22phox and SGK1. Dietary salt reduction after a 4-week high-salt diet decreased both blood pressure and proteinuria, but was associated with significantly higher proteinuria than in normal control rats at 4 weeks after salt reduction. Administration of tempol during high-salt feeding, or eplerenone, an MR antagonist (100 mg/kg/day), started after salt reduction, recovered proteinuria to normal levels at 4 weeks after salt reduction. Paraquat, a reactive oxygen species generator, enhanced MR transcriptional activity in cultured rat mesangial cells and mouse podocytes. CONCLUSIONS These results suggest that oxidative stress plays an important role in glomerular MR activation in Dahl salt-sensitive rats. Persistent MR activation even after reducing salt intake could limit the beneficial effects of salt restriction.
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Affiliation(s)
- Kento Kitada
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Ya Liu
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | | | - Hirofumi Hitomi
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Yuki Shibayama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Hirotaka Shibata
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Yukiko Nagai
- Life Sciences Research Center, Kagawa University, Kagawa, Japan
| | - Hirohito Mori
- Department of Gastroenterology, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology, Kagawa University, Kagawa, Japan
| | - Hiroyuki Kobori
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
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50
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Lei B, Nakano D, Fan YY, Kitada K, Hitomi H, Kobori H, Mori H, Masaki T, Nishiyama A. Add-on aliskiren elicits stronger renoprotection than high-dose valsartan in type 2 diabetic KKAy mice that do not respond to low-dose valsartan. J Pharmacol Sci 2012; 119:131-8. [PMID: 22673148 DOI: 10.1254/jphs.12031fp] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren.
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Affiliation(s)
- Bai Lei
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
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