Recent insights into diabetic renal injury from the db/db mouse model of type 2 diabetic nephropathy.

Abstract

The db/db mouse is the most widely used animal model of type 2 diabetic nephropathy. Recent studies have utilized genetic backcrossing with transgenic mouse strains to create novel db/db strains that either lack or overexpress specific genes. These novel strains [ICAM-1-/-, CCL2-/-, MKK3-/-, osteopontin-/-, plasminogen activator inhibitor-1 (PAI-1)-/-, endothelial nitric oxide synthase-/-, SOD-Tg, rCAT-Tg] have provided valuable insights into the molecular mechanisms which promote diabetic renal injury. In addition, surgical removal of one kidney has been shown to accelerate injury in the remaining kidney of diabetic db/db mice. A number of novel therapeutic agents have also been tested in db/db mice, including inhibitors of inflammation (chemokine receptor antagonists, anti-CCL2 RNA aptamer, anti-c-fms antibody); oxidative stress (oxykine, biliverdin); the renin-angiotensin-aldosterone system (aliskiren, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, eplerenone); advanced glycation end products (AGE; pyridoxamine, alagebrium, soluble AGE receptor); angiogenesis (NM-3, anti-CXCL12 RNA aptamer, soluble Flt-1); lipid accumulation (statins, farnesoid X receptor agonists, Omacor); intracellular signaling pathways (PKC-β or JNK inhibitors); and fibrosis [transforming growth factor (TGF)-β antibody, TGF-βR kinase inhibitor, soluble betaglycan, SMP-534, CTGF-antisense oligonucleotide, mutant PAI-1, pirfenidone], which have identified potential therapeutic targets for clinical translation. This review summarizes the advances in knowledge gained from studies in genetically modified db/db mice and treatment of db/db mice with novel therapeutic agents.

• Authors: G H Tesch, A K H Lim
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 300 Issue 2 Pg. F301-10 (Feb 2011) ISSN: 1522-1466 [Electronic] United States
• PMID: 21147843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Plasminogen Activator Inhibitor 1
• Spp1 protein, mouse
• Osteopontin
• Intercellular Adhesion Molecule-1
• Nitric Oxide Synthase Type III
• MAP Kinase Kinase 3
• Map2k3 protein, mouse

Topics

• Animals
• Chemokine CCL2 (genetics)
• Diabetes Mellitus, Type 2 (complications)
• Diabetic Nephropathies (drug therapy, enzymology, genetics, surgery)
• Disease Models, Animal
• Female
• Inflammation (drug therapy, genetics)
• Intercellular Adhesion Molecule-1 (genetics)
• MAP Kinase Kinase 3 (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type III (genetics)
• Osteopontin (genetics)
• Plasminogen Activator Inhibitor 1 (genetics)
• Renin-Angiotensin System (drug effects, genetics)