Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes

Kidney Int. 2010 Jun;77(11):1000-9. doi: 10.1038/ki.2010.22. Epub 2010 Feb 24.

Abstract

We recently showed that losartan and paricalcitol are synergistic in the treatment of diabetic nephropathy in a model of type 1 diabetes. To test this strategy in a model of type 2 diabetes, we treated 2-month-old diabetic Lprdb/db mice with losartan, paricalcitol, or a combination of losartan and paricalcitol for 3 months. Vehicle-treated diabetic mice developed progressive albuminuria and glomerular abnormalities with mesangial expansion and glomerulosclerosis compared to their non-diabetic littermate control mice. Accompanying damage of the glomerular filtration barrier was a marked reduction in podocyte number as well as reduced expression of slit diaphragm proteins. Further, there was increased glomerular expression of extracellular matrix proteins, monocyte chemoattractant protein-1 and transforming growth factor-beta. Losartan or paricalcitol each alone moderately ameliorated albuminuria and glomerular damage. However, their combined use showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduced synthesis of extracellular matrix proteins, and reduction of glomerulosclerosis. These effects were accompanied by blockade of the compensatory increase of renin production and angiotensin I/II accumulation in the kidney. Thus, our study further shows that vitamin D analogs can increase the efficacy of AT1 receptor blockade, leading to a more effective prevention of kidney disease in type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Albuminuria / genetics
  • Albuminuria / metabolism
  • Albuminuria / pathology
  • Albuminuria / prevention & control*
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Biomarkers / blood
  • Biomarkers / urine
  • Blood Urea Nitrogen
  • Creatinine / blood
  • Creatinine / urine
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Disease Models, Animal
  • Disease Progression
  • Drug Synergism
  • Drug Therapy, Combination
  • Ergocalciferols / pharmacology*
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation / drug effects
  • Inflammation Mediators / metabolism
  • Kidney Glomerulus / drug effects*
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Losartan / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / metabolism
  • Receptors, Leptin / genetics
  • Renin-Angiotensin System / drug effects
  • Time Factors
  • Vitamins / pharmacology*

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Biomarkers
  • Ergocalciferols
  • Extracellular Matrix Proteins
  • Inflammation Mediators
  • RNA, Messenger
  • Receptors, Leptin
  • Vitamins
  • leptin receptor, mouse
  • paricalcitol
  • Creatinine
  • Losartan