title: Hyperglycemia and renin-dependent hypertension synergize to model diabetic nephropathy.
abstract: Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocin-induced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in human diabetic nephropathy. In conclusion, although induction of diabetes alone in rodents has limited utility to model human diabetic nephropathy, renin-dependent hypertension and hyperglycemia synergize to recapitulate many of the clinical, histological, and gene expression changes observed in humans.
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK. bryan.conway@ed.ac.uk
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
authors.forename: Jillian
authors.initials: J
authors.lastname: Rennie
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dunbar
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Manning
authors.forename: Christopher O
authors.initials: CO
authors.lastname: Bellamy
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000652:urine; D000818:Animals; D015897:Comorbidity; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000453:epidemiology; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology / Q000652:urine; D004195:Disease Models, Animal; D005355:Fibrosis; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000150:complications* / Q000453:epidemiology; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000453:epidemiology; D007211:Indoles / Q000009:adverse effects; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D007211:Indoles; C473112:Ren2 protein, mouse; D013311:Streptozocin; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D012083:Renin