Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats

Am J Physiol Renal Physiol. 2015 Jun 15;308(12):F1386-97. doi: 10.1152/ajprenal.00593.2013. Epub 2014 Dec 17.


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.

Keywords: claudin-16; diabetic nephropathy; distal convoluted tubule; hypermagnesiuria; transient receptor potential M6; tubulointerstitial nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetic Nephropathies / metabolism*
  • Down-Regulation / physiology
  • Insulin Resistance / physiology
  • Male
  • Obesity / metabolism*
  • Rats, Inbred OLETF
  • Renal Tubular Transport, Inborn Errors / metabolism*
  • TRPM Cation Channels / metabolism*


  • Blood Glucose
  • TRPM Cation Channels
  • TRPM6 protein, rat

Supplementary concepts

  • Hypomagnesemia 4, Renal