Mesangial cells from diabetic NOD mice constitutively express increased density of atrial natriuretic peptide C receptors

Kidney Int. 1999 Apr;55(4):1293-302. doi: 10.1046/j.1523-1755.1999.00393.x.


Background: Experimental evidence shows that natriuretic peptides (NPs) play a pathophysiological role in the glomerular hemodynamic abnormalities that occur in diabetes mellitus.

Methods: In this study, the cGMP response to NPs and the different subtypes of NP receptors were examined in mesangial cells derived from a genetic model of diabetes, the nonobese diabetic (NOD) mouse. Multiple mesangial cell lines were derived from diabetic (D-NOD) and nondiabetic (ND-NOD) adult mice and were studied at different passages.

Results: cGMP accumulation after stimulation by atrial NP (ANP) or C-type NP (CNP) was markedly inhibited in D-NOD cells irrespective of the glucose concentration (6 or 20 mM) in the culture medium. In contrast, NP receptor density measured from [125I]-ANP saturation binding curves was 7.5 times greater in D-NOD than in ND-NOD cells. No change in KD (200 pM in both cell lines) was observed. Competitive inhibition studies showed that 4-23 C-ANP, which is specific of clearance receptors (NPR-C), displaced 90% of the maximum fraction bound, suggesting the predominance of NPR-C in both cell lines. Further identification was obtained from RNase protection assay and reverse transcription-polymerase chain reaction, which also demonstrated the higher expression of NPR-C mRNA in D-NOD cells. In contrast, NPR-A mRNA was not modified. Increased expression of NPR-C in D-NOD cells was associated with an increase of ANP internalization rate at 37 degrees C, indicating that these receptors were functional.

Conclusions: These studies demonstrate that the constitutive overexpression of NPR-C in D-NOD mesangial cells is associated with a decreased response of cGMP to ANP or CNP treatment. This could be due to the lesser availability of the peptides for binding to NPR-A or NPR-B or to an inhibitory effect on NP-dependent guanylate cyclase activity via the activation of NPR-C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / metabolism
  • Atrial Natriuretic Factor / pharmacology
  • Binding, Competitive / drug effects
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Female
  • Gene Expression
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / metabolism*
  • Guanylate Cyclase / metabolism*
  • Insulin-Like Growth Factor I / metabolism
  • Ligands
  • Mice
  • Mice, Inbred NOD
  • Peptide Fragments / pharmacology
  • RNA, Messenger / metabolism
  • Receptors, Atrial Natriuretic Factor / metabolism*
  • Time Factors


  • Ligands
  • Peptide Fragments
  • RNA, Messenger
  • atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-
  • Insulin-Like Growth Factor I
  • Atrial Natriuretic Factor
  • Guanylate Cyclase
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor C
  • Cyclic GMP