Kidney Disease Marta Crespo and Clara Barrios

Experimental and clinical diabetic nephropathy

Area consolidated by the ISCIII with 4 projects in the periods 2008-2011, 2012-2014 and 2015-2017 (PI Dra. MJ.Soler), and one in 2017-2019 (Dra. Clara Barrios). Thanks to the competitive grant PERIS (Plan estratégico de investigación e innovación en salud) managed by AQuAS, Dr. Barrios is enjoying a two-year intensification period to dedicate herself fully to clinical and basic research.

The initial study described the importance of ACE2 in experimental diabetic nephropathy in the diabetic NOD mouse; the role of insulin in ACE2 expression in podocytes; the relationship of ACE2 with a history of ischaemic heart disease and with graft function in renal transplant recipients; and the relationship with cardiac infarction dimension, late ventricular function and the presence of adverse remodelling.

We also study the effect of sex differences in diabetic nephropathy in mice with ACE2 deletion and the characterisation of the renin angiotensin system in diabetic patients with chronic kidney disease. In a publication that has been cited more than 100 times in international scientific journals, we demonstrated that the distribution and activity of ACE and ACE2 varies depending on the tissue studied.

As a group comprising mainly doctors with an interest in clinical and translational research, we are part of the NEFRONA project (National Observatory of Atherosclerosis in Nephrology), which has allowed us to study the role of ECA2 and ADAM17 in this patient cohort.

We have also contributed to the knowledge of the role ADAM17 plays in experimental diabetic nephropathy, demonstrating its participation in the appearance of fibrosis and renal inflammation. Further work in this area involves studies in tubular cell culture, either in primary culture or in 3D culture, which allow us to demonstrate our hypotheses related to diabetic renal lesions.

This research area is completed by the ongoing project of Dr. Barrios (PI16/00620). Diabetic kidney disease (DKD) is the only complication of diabetes that is not decreasing in incidence and is the leading cause of advanced kidney damage in Western countries.

Numerous pathophysiological pathways are involved in this renal damage, so a global approach is needed rather than focusing specifically on a single pathway. High-throughput technologies that detect metabolites and protein glycosylation can identify diagnostic and prognostic markers of DKD.

Currently, biomarkers such as serum creatinine and albuminuria, used to assess renal function, have well-known limitations such as lack of sensitivity in the early stages of chronic renal failure. For this reason, we carried out a longitudinal study of metabolomic, lipidomic and glycomic profiles in a population of 700 type-2 diabetes patients with different degrees of renal impairment: a complete analysis at baseline and another at 5 years, in order to establish hypotheses of association between the different profiles and the eventual progressive deterioration of renal function. Our findings will be bolstered by trying to replicate the results in three different European cohorts. To date, metabolomic profiles have been determined using 1H-MRI (Nightingale Health Ltd), total IgG glycosylation (ultra-high performance liquid chromatography) and circulating galectin-3 (ELISA).