In mineralocorticoid receptor activation an important driver in progression of chronic kidney disease in the cat?

Chronic kidney disease (CKD) is a very common problem in cats, increasing in prevalence with age and resulting in significant morbidity and mortality in ~ 50% of cases, where death can be attributed to poor quality of life. At diagnosis, the initiating cause(s) is usually not evident and the predominant pathology is multifocal to segmental interstitial fibrosis and tubulointerstitial inflammation. Proteinuria, low red cell mass and high plasma phosphate are epidemiological risk factors for progression of feline CKD and are associated with the severity of interstitial fibrosis. Renal mass reduction models in the cat replicate these lesions in the remnant kidney with the pathology being exacerbated by renal wrapping to activate the renin-angiotensin-aldosterone system. Similar lesions can also be induced by a single bout of ischaemia, suggesting repeated bouts of hypoxia might be important in initiating and perpetuating fibrosis and chronic inflammation in the kidneys of cats.
Thus, experimental and epidemiological evidence in the cat supports the hypothesis that repeated bouts of hypoxia could contribute to progressive renal injury and stimulate the multifocal to segmental fibrosis that is characteristic of feline CKD. Laboratory animal models of renal ischaemia also show progression of tubulointerstitial fibrosis and in this scenario aldosterone is a contributory factor in the progressive pathology. Antagonists of the mineralocorticoid receptor (MR), including spironolactone, reduce the chronic pathology if administered during or immediately post ischaemia.
We aim to explore the role of the MR in feline CKD progression and test the hypotheses that:
1. MR expression and activation occurs in feline CKD and is associated with fibrosis and tissue hypoxia
2. MR expression and activation is associated with progressive CKD in the cat
3. MR antagonists will reduce active and progressive fibrosis in cats with progressive CKD

To test these hypotheses we will use the large RVC database of feline CKD case records and associated archived plasma, urine and kidney samples. Fresh frozen kidney tissue from cats with progressive CKD will be compared to tissue from normal cats and those with non-progressive CKD. MR expression will be measured by immunohistochemistry and qRT-PCR and MR activation will be assessed by measurement of phosphorylated SGK-1 (protein expression). These measures of MR activation will be related to renal pathology and urinary active TGF-beta1 from urine samples collected prior to euthanasia and to tissue expression of hypoxia pathway activation.