Glutathione transferase kappa deficiency causes glomerular nephropathy without overt oxidative stress

Glutathione transferase kappa (GSTK1-1) is a highly conserved, mitochondrial enzyme potentially involved in redox reactions. GSTK1-1-deficient mice were generated to further study the enzyme's biological role. Reduced and total glutathione levels in liver and kidney were unchanged by GSTK1-1 deficiency and NADPH quinone oxidoreductase 1 expression was not elevated indicating that there is no general underlying oxidative stress in Gstk1 / mice. Electron microscopy of liver and kidney showed no changes in mitochondrial morphology with GSTK1-1 deficiency. The death of a number of Gstk1 / males with urinary tract problems prompted close examination of the kidneys. Electron microscopy revealed glomerular basement membrane changes at 3 months, accompanied by detectable microalbuminuria in male mice (albumin:creatinine ratio of 2.660.83 vs 1.130.20 mg/mmol for Gstk1 / and wild-type (WT), respectively, P0.001). This was followed by significant foot process effacement (40-55% vs 10% for Gstk1 / and WT, respectively) at 6 months of age in all Gstk1 / mice examined. Kidney tubules were ultrastructurally normal. Compared with human disease, the Gstk1 / kidneys show changes seen in glomerulopathies causing nephrotic syndrome. Gstk1 / mice may offer insights into the early development of glomerular nephropathies.