Characterization of the development of renal injury in Type-1 diabetic Dahl salt-sensitive rats

Am J Physiol Regul Integr Comp Physiol. 2013 Oct 1;305(7):R727-34. doi: 10.1152/ajpregu.00382.2012. Epub 2013 Aug 7.

Abstract

The present study compared the progression of renal injury in Sprague-Dawley (SD) and Dahl salt-sensitive (SS) treated with streptozotocin (STZ). The rats received an injection of STZ (50 mg/kg ip) and an insulin pellet (2 U/day sc) to maintain the blood glucose levels between 400 and 600 mg/dl. Twelve weeks later, arterial pressure (143 ± 6 vs. 107 ± 8 mmHg) and proteinuria (557 ± 85 vs. 81 ± 6 mg/day) were significantly elevated in STZ-SS rats compared with the values observed in STZ-SD rats, respectively. The kidneys from STZ-SS rats exhibited thickening of glomerular basement membrane, mesangial expansion, severe glomerulosclerosis, renal interstitial fibrosis, and occasional glomerular nodule formation. In additional studies, treatment with a therapeutic dose of insulin (4 U/day sc) attenuated the development of proteinuria (212 ± 32 mg/day) and renal injury independent of changes in arterial pressure in STZ-SS rats. Since STZ-SS rats developed severe renal injury, we characterized the time course of changes in renal hemodynamics during the progression of renal injury. Nine weeks after diabetes onset, there was a 42% increase in glomerular filtration rate in STZ-SS rats vs. time-control SS rats with reduced renal blood flow. These results indicate that SS rats treated with STZ develop hyperfiltration and progressive proteinuria and display renal histological lesions characteristic of those seen in patients with diabetic nephropathy. Overall, this model may be useful to study signaling pathways and mechanisms that play a role in the progression of diabetes-induced renal disease and the development of new therapies to slow the progression of diabetic nephropathy.

Keywords: Dahl S rats; Type 1 diabetes; diabetes-associated renal disease; glomerulosclerosis; hyperfiltration; renal fibrosis; renal hemodynamics; streptozotocin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterial Pressure
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / physiopathology
  • Diabetic Nephropathies / prevention & control
  • Disease Progression
  • Drug Implants
  • Fibrosis
  • Glomerular Filtration Rate
  • Hypoglycemic Agents / administration & dosage
  • Insulin / administration & dosage
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney / physiopathology
  • Male
  • Proteinuria / etiology
  • Proteinuria / pathology
  • Rats
  • Rats, Inbred Dahl
  • Rats, Sprague-Dawley
  • Streptozocin
  • Time Factors

Substances

  • Blood Glucose
  • Drug Implants
  • Hypoglycemic Agents
  • Insulin
  • Streptozocin