title: Specific MAPK inhibitors prevent hyperglycemia-induced renal diseases in type 1 diabetic mouse model.
abstract: Mitogen-activated protein kinase (MAPK) and renin-angiotensin system (RAS) play critical roles in the process of renal diseases, but their interaction has not been comprehensively discussed. In the present studies, we investigated the renoprotective effects of MPAK inhibitors on renal diseases in type 1 diabetic mouse model, and clarify the crosstalk among MAPK signaling. Type 1 diabetic mouse model was established in male C57BL/6 J mice, and treated with or without 10 mg/kg MAPK blockers, including ERK inhibitor PD98059, p38 inhibitor SB203850, and JNK inhibitor SP600125 for four weeks. Hyperglycemia induced renal injuries, but treating them with MAPK inhibitors significantly decreased glomerular volume and glycogen in renal tissues. Although slightly changed body weight and fasting blood glucose levels, MAPK inhibitors attenuated blood urea nitrogen, urea protein, and microalbuminuria. Administration also reduced the diabetes-induced RAS activation, including angiotensin II converting enzyme (c) and Ang II, which contributed to its renal protective effects in the diabetic mice. In addition, the anti-RAS of MAPK inhibitor treatment markedly reduced gene expression of tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase, fibrotic accumulation, and transforming growth factor-β1 levels in renal tissues. Furthermore, chemical inhibitors and genetic siRNA results identified the crosstalk among the three MAPK signaling, and proved JNK signaling played a critical role in MAPK-mediated ACE pathway in hyperglycemia state. Collectively, these results support the therapeutic effects of MAPK-specific inhibitors, especially JNK inactivation, on hyperglycemia-induced renal damages.
authors.affiliation: Department of Urology, Tongji Hospital, School of Medicine, Tongji University, XinChun Road 389, Shanghai, 200065, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, Wannan Medical College, Wuhu Anhui, People's Republic of China.
authors.forename: Zongyuan
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Urology, Tongji Hospital, School of Medicine, Tongji University, XinChun Road 389, Shanghai, 200065, People's Republic of China. wudenglong2013@126.com.
authors.forename: Denglong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, People's Republic of China. hezrnie@hotmail.com.
authors.forename: Hezhongrong
authors.initials: H
authors.lastname: Nie
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D051379:Mice
chemical_list: D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Mitogen-activated protein kinase; Renal diseases; Renin–angiotensin system; Type 1 diabetes