Is 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) 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.

Complementary in vitro studies conducted in parallel will determine the effects of MR activation on the responses of cultured feline renal tubular epithelial cells and renal fibroblasts to TGFβ-1. Proteomic and transcriptomic approaches will be used within the in vitro studies to identify potential in vivo markers of MR activation and active fibrosis. Feline urine samples will be screened to determine whether these markers could be used to identify clinical patients with activation of MRs and hypoxia related pathways for entry into the clinical trial.

This project is ideal for a veterinary graduate who is curious to discover innovative ways to diagnose progressive CKD in cats and to use cutting-edge biological science in biomarker discovery. The project will give the opportunity to design a clinical trial to determine whether the pathways identified as being activated in tissue obtained at post-mortem are driving the pathological processes leading to progression in vivo. The successful candidate will benefit from the support of a well established clinical research group, the excellent training the LIDo programme has to offer and the opportunity to work with scientists in industry.

The student will use the laboratory studies to help design a pilot proof of concept clinical trial run by the company to determine whether clinical doses of spironolactone reduce evidence of active fibrosis in cats with CKD that have been selected for entry into the pilot study because they have marked evidence of activation of renal MR based on their urinary proteome