Olmesartan Prevents Microalbuminuria in db/db Diabetic Mice Through Inhibition of Angiotensin II/p38/SIRT1-Induced Podocyte Apoptosis

Background/Aims: Blockage of the renin-angiotensin II system (RAS) prevents or delays albuminuria in diabetic patients. The aim of this study was to investigate the inhibitory mechanism of the angiotensin receptor blocker olmesartan on albuminuria in a murine model of diabetic nephropathy. Methods: Male db/db diabetic mice were fed with placebo or 20 mg/kg olmesartan by daily gavage for 12 weeks. Conditionally immortalized mouse podocytes were treated with glucose, angiotensin II, olmesartan or p38 inhibitor s8307 in different experimental conditions after differentiation. Results: Olmesartan reduced albuminuria in db/db mice without change in body weight and glycemia. The increase of apoptotic cells and decrease of podocytes in the diabetic glomerulus were prevented by olmesartan. Moreover, olmesartan restored silent mating type information regulation 1 (SIRT1) expression in diabetic glomeruli. Furthermore, olmesartan treatment suppressed p38 phosphorylation but did not restore adenosine 5‘-monophosphate-activated protein kinase (AMPK) phosphorylation in the diabetic glomerulus. In vitro study revealed that olmesartan prevented angiotensin II/p38/SIRT1 induced podocyte apoptosis, but it only slightly prevented high glucose/AMPK/SIRT1 induced podocyte apoptosis. In addition, the p38 inhibitor s8307 reversed SIRT1 expression and angiotensin II induced podocyte apoptosis. Conclusions: Olmesartan reduced albuminuria in diabetic nephropathy through inhibiting angiotensin II/p38/SIRT1 triggered podocyte apoptosis.

[1]  S. Tang,et al.  Diabetic nephropathy: landmark clinical trials and tribulations. , 2016, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  Yong Li,et al.  Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1α axis in vitro. , 2016, Food & function.

[3]  G. Bakris,et al.  Management of Hypertension in Diabetic Nephropathy: How Low Should We Go? , 2016, Blood Purification.

[4]  P. Guarino,et al.  BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial. , 2015, Clinical journal of the American Society of Nephrology : CJASN.

[5]  H. Kobori,et al.  Regression of Glomerular and Tubulointerstitial Injuries by Dietary Salt Reduction with Combination Therapy of Angiotensin II Receptor Blocker and Calcium Channel Blocker in Dahl Salt-Sensitive Rats , 2014, PloS one.

[6]  Ming-Ming Zhou,et al.  Role of Transcription Factor Acetylation in Diabetic Kidney Disease , 2014, Diabetes.

[7]  W. Kuo,et al.  ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation , 2014, Cell Death and Differentiation.

[8]  A. Cheung,et al.  Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation. , 2014, Clinical science.

[9]  M. Roth,et al.  Sorting out functions of sirtuins in cancer , 2014, Oncogene.

[10]  Qiong Yuan,et al.  Advanced glycation end‐products impair Na+/K+‐ATPase activity in diabetic cardiomyopathy: Role of the adenosine monophosphate‐activated protein kinase/sirtuin 1 pathway , 2014, Clinical and experimental pharmacology & physiology.

[11]  H. Kobori,et al.  Calcium Channel Blocker Enhances Beneficial Effects of an Angiotensin II AT1 Receptor Blocker against Cerebrovascular-Renal Injury in type 2 Diabetic Mice , 2013, PloS one.

[12]  F. Lovat,et al.  Angiotensin-converting-enzyme inhibition counteracts angiotensin II-mediated endothelial cell dysfunction by modulating the p38/SirT1 axis , 2013, Journal of hypertension.

[13]  M. Sobieszczańska,et al.  Nephroprotective action of sirtuin 1 (SIRT1) , 2013, Journal of Physiology and Biochemistry.

[14]  E. Vivian,et al.  Therapeutic approaches to slowing the progression of diabetic nephropathy – is less best? , 2013, Drugs in context.

[15]  T. Ha,et al.  Angiotensin II suppresses adenosine monophosphate-activated protein kinase of podocytes via angiotensin II type 1 receptor and mitogen-activated protein kinase signaling , 2013, Clinical and Experimental Nephrology.

[16]  I. Shimomura,et al.  Telmisartan ameliorates insulin sensitivity by activating the AMPK/SIRT1 pathway in skeletal muscle of obese db/db mice , 2012, Cardiovascular Diabetology.

[17]  Ping Zhang,et al.  Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury. , 2012, Kidney international.

[18]  C. Chatzikyrkou,et al.  Update on the ROADMAP clinical trial report: olmesartan for the prevention or delay of microalbuminuria development in Type 2 diabetes , 2012, Expert review of cardiovascular therapy.

[19]  Shilin Yang,et al.  Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice. , 2012, American journal of physiology. Renal physiology.

[20]  S. Ito,et al.  Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats , 2012, American journal of hypertension.

[21]  L. Ruilope,et al.  Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. , 2011, The New England journal of medicine.

[22]  G. Tesch,et al.  Recent insights into diabetic renal injury from the db/db mouse model of type 2 diabetic nephropathy. , 2011, American journal of physiology. Renal physiology.

[23]  S. Kume,et al.  Resveratrol Improves Oxidative Stress and Protects Against Diabetic Nephropathy Through Normalization of Mn-SOD Dysfunction in AMPK/SIRT1-Independent Pathway , 2011, Diabetes.

[24]  S. Ito,et al.  Regression of superficial glomerular podocyte injury in type 2 diabetic rats with overt albuminuria: effect of angiotensin II blockade , 2010, Journal of hypertension.

[25]  C. Hao,et al.  Sirtuins and their relevance to the kidney. , 2010, Journal of the American Society of Nephrology : JASN.

[26]  Su-Jae Lee,et al.  Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase* , 2009, The Journal of Biological Chemistry.

[27]  T. Kita,et al.  Urinary Smad1 Is a Novel Marker to Predict Later Onset of Mesangial Matrix Expansion in Diabetic Nephropathy , 2008, Diabetes.

[28]  B. Viollet,et al.  A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. , 2007, American journal of physiology. Renal physiology.

[29]  P. Puigserver,et al.  Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α , 2006, Cell.

[30]  T. Kita,et al.  Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy , 2006, Laboratory Investigation.

[31]  M. Nangaku,et al.  Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. , 2005, Journal of the American Society of Nephrology : JASN.

[32]  R. Atkins,et al.  Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy , 2004, Diabetologia.

[33]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[34]  W. Wilmer,et al.  Chronic exposure of human mesangial cells to high glucose environments activates the p38 MAPK pathway. , 2001, Kidney international.

[35]  S. Hawley,et al.  Characterization of the AMP-activated Protein Kinase Kinase from Rat Liver and Identification of Threonine 172 as the Major Site at Which It Phosphorylates AMP-activated Protein Kinase* , 1996, The Journal of Biological Chemistry.

[36]  C. Park,et al.  Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice , 2012, Diabetologia.

[37]  D. Féliers,et al.  Resveratrol ameliorates high glucose-induced protein synthesis in glomerular epithelial cells. , 2010, Cellular signalling.

[38]  Steven P Gygi,et al.  Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. , 2005, Nature.

[39]  I. G. Fantus,et al.  High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growth factor. , 2002, American journal of physiology. Endocrinology and metabolism.

[40]  CALL FOR PAPERS Novel Therapeutics in Renal Diseases Theobromine increases NAD (cid:2) /Sirt-1 activity and protects the kidney under diabetic conditions , 2022 .