title: Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats.
abstract: We assessed the expression profile of Mg(2+)-transporting molecules in obese diabetic rats as a cause of hypermagnesiuric hypomagnesemia, which is involved in the development of insulin resistance, hypertension, and coronary diseases. Kidneys were obtained from male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) obese diabetic rats at the ages of 16, 24, and 34 wk. Expression profiles were studied by real-time PCR and immunohistochemistry together with measurements of urine Mg(2+) excretion. Urine Mg(2+) excretion was increased in 24-wk-old OLETF rats and hypomagnesemia was apparent in 34-wk-old OLETF rats but not in LETO rats (urine Mg(2+) excretion: 0.16 ± 0.01 μg·min(-1)·g body wt(-1) in 24-wk-old LETO rats and 0.28 ± 0.01 μg·min(-1)·g body wt(-1) in 24-wk-old OLETF rats). Gene expression of transient receptor potential (TRP)M6 was downregulated (85.5 ± 5.6% in 34-wk-old LETO rats and 63.0 ± 3.5% in 34-wk-old OLETF rats) concomitant with Na(+)-Cl(-) cotransporter downregulation, whereas the expression of claudin-16 in tight junctions of the thick ascending limb of Henle was not different. The results of the semiquantitative analysis of immunohistochemistry were consistent with these findings (TRPM6: 0.49 ± 0.04% in 16-wk-old LETO rats, 0.10 ± 0.01% in 16-wk-old OLETF rats, 0.52 ± 0.03% in 24-wk-old LETO rats, 0.10 ± 0.01% in 24-wk-old OLETF rats, 0.48 ± 0.02% in 34-wk-old LETO rats, and 0.12 ± 0.02% in 34-wk-old OLETF rats). Gene expression of fibrosis-related proinflammatory cytokines as well as histological changes showed that the hypermagnesiuria-related molecular changes and tubulointerstitial nephropathy developed independently. TRPM6, located principally in distal convoluted tubules, appears to be a susceptible molecule that causes hypermagnesiuric hypomagnesemia as a tubulointerstitial nephropathy-independent altered tubular function in diabetic nephropathy.
authors.affiliation: Ishikawa Kinenkai Kawagoe Ekimae Clinic, Kawagoe, Saitama, Japan; Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan;
authors.forename: Kaori
authors.initials: K
authors.lastname: Takayanagi
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan;
authors.forename: Taisuke
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan;
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tayama
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
authors.affiliation: Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan;
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Iwashita
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan;
authors.forename: Juko
authors.initials: J
authors.lastname: Asakura
authors.affiliation: Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan;
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitarai
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan; hase2126@saitama-med.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D009765:Obesity / Q000378:metabolism*; D020334:Rats, Inbred OLETF; D015499:Renal Tubular Transport, Inborn Errors / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D050053:TRPM Cation Channels; C507531:TRPM6 protein, rat
keywords: claudin-16; diabetic nephropathy; distal convoluted tubule; hypermagnesiuria; transient receptor potential M6; tubulointerstitial nephropathy