Proteinuria as a determinant of renal expression of heme oxygenase-1: studies in models of glomerular and tubular proteinuria in the rat.
Heme oxygenase-1 (HO-1), a cytoprotective gene, is commonly induced in renal tubules in the diseased kidney. Because proteinuria is a hallmark for kidney disease, we examined the relationship between proteinuria and tubular induction of HO-1, specifically questioning whether increased trafficking of protein across the renal tubular epithelium, as a consequence of proteinuria, induces tubular expression of HO-1. We examined a model of glomerular proteinuria induced by daily injections of BSA, which is associated with increased tubular uptake of filtered protein, and a model of tubular proteinuria induced by maleate, the latter exhibiting decreased tubular uptake and trafficking of protein. The BSA model of glomerular proteinuria failed to exhibit induction of HO-1; HO-1 was not induced in proximal tubular epithelial cells exposed to BSA. In contrast, in maleate nephropathy wherein tubular uptake of protein is decreased because of generalized proximal tubular injury induced by maleate, HO-1 was strongly induced in proximal tubules; inhibition of HO activity in maleate nephropathy worsened proteinuria, renal histological injury, and apoptosis. In renal proximal tubular epithelial cells, maleate induced HO-1 and caused apoptosis, the latter increased when HO activity was inhibited. From these studies, we conclude that expression of HO-1 in the diseased kidney cannot be ascribed to the tubular uptake and metabolism of protein such as albumin, and that the expression of HO-1 in a model of tubular proteinuria reflects a functionally significant stress response to toxin-induced proximal tubular injury.
Pedraza-Chaverri
José
J
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Murali
Narayana S
NS
Croatt
Anthony J
AJ
Alam
Jawed
J
Grande
Joseph P
JP
Nath
Karl A
KA
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000201:enzymology / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D008298:Maleates; D011507:Proteinuria / Q000139:chemically induced / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine
D008298:Maleates; D012710:Serum Albumin, Bovine; C030272:maleic acid; D051547:Heme Oxygenase-1