Endocrine Abstracts

Renal functions in a mouse model of Cushing’s Syndrome have been characterised by analysing RNA expression complemented by immunohistochemistry studies. A microarray of kidneys from mice infused with ACTH for two weeks identified gene transcripts that were up-regulated (70) and down-regulated (49) more than two-fold. Four separate clusters of closely correlated genes (r> 0.97; P< 0.001) were investigated in more detail. One down-regulated cluster included histocompatibility genes (H2-Aa, H2-Ab1, H2-Eb1, ii) and others associated with hypertension-induced inflammation (adipsin, apelin, angiotensin converting enzyme). This anti-inflammatory phenotype was confirmed by immunostaining for the macrophage marker F4/80: fewer positive cells were associated with renal medulla and glomerular regions. A separate down-regulated cluster included bcat, p311, rnf24 and tgm1 which could be linked to a decrease in tubular cell proliferation and/or fibrosis. Numbers of Ki67 labelled proliferating cells were significantly less in the outer cortex of ACTH-treated kidneys but there was no evidence of glomerulosclerotic changes. One cohort of up-regulated genes included several linked to mineralocorticoid excess (p21, ztbt16) and others known to be associated with nephropathy (fgg, fga, tpa). Immunohistochemistry confirmed protein matched mRNA patterns for representatives of this group (arg2, slc13a1) and localised expression to proximal tubules. The second up-regulated cluster included those known to be controlled by glucocorticoids (fkpbp, gilz, sult1a1, agpt3 and 4). Based on previous studies, this up-regulated cluster might reflect glucocorticoid-induced changes in podocytes which in turn would explain the albuminuria which has been noted in this model of Cushings. In summary ACTH inhibited expression of some genes commonly associated with inflammation and fibrosis and promoted the expression of others that cause nephropathy and proteinuria. There is evidence that these positive and negative outcomes are, in part, differentiated as mineralocorticoid and glucocorticoid-regulated processes.