title: Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy.
abstract: Little is known about role of PDE4 in the development and progression of diabetic nephropathy. Here, we investigated the effect of roflumilast, a selective PDE 4 inhibitor in type 1 diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats using streptozotocin (55 mg/kg). Diabetic rats showed elevated plasma glucose, blood urea nitrogen, creatinine and decrease in plasma albumin confirming signs of nephropathy. Roflumilast at 2 and 3mg/kg normalized these alterations. Roflumilast also suppressed oxidative stress and deposition of an extracellular matrix protein such as fibronectin and collagen in kidney of diabetic rats. TUNEL assay revealed apoptosis in diabetic kidney than control and that roflumilast prevents this effect. We show that kidney of diabetic rats displayed a state of p-AMPK and SIRT1 deficiency and that roflumilast, interestingly, was able to restore their levels. Further, roflumilast prevented an increase in HO-1 and loss in the FoxO1 expression in diabetes. However, it did not improve the reduced NRF2 levels in diabetes. This is the first report to show that, like resveratrol and other SIRT1 activators, roflumilast also mimics calorie restriction effects through activation of AMPK/SIRT1 and protects against diabetic nephropathy. This study unveils the unexplored potential of roflumilast which can be used in treatment of metabolic disorders.
authors.affiliation: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India. Electronic address: tikoo.k@gmail.com.
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Tikoo
authors.affiliation: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Saritha
authors.initials: S
authors.lastname: Lodea
authors.affiliation: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Pinakin Arun
authors.initials: PA
authors.lastname: Karpe
authors.affiliation: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000631:Aminopyridines / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D031204:Caloric Restriction; D003404:Creatinine / Q000097:blood; D003521:Cyclopropanes / Q000627:therapeutic use; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D020287:In Situ Nick-End Labeling; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D001786:Blood Glucose; D003521:Cyclopropanes; C424423:Roflumilast; D003404:Creatinine; D000263:Adenylate Kinase; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: AMPK and SIRT1; Calorie restriction; Diabetic nephropathy; PDE4