IMIM - Institut Hospital del Mar d'Investigacions Mèdiques

Kidney Disease Julio Pascual

Tornar

Pathogenesis of Diabetic Nephropathy

The angiotensin-converting enzyme 2 (ACE2) and its role in diabetic kidney Nephropathy

Diabetic Nephropathy (DN) is the main cause of terminal chronic kidney failure in developed countries. Blocking the Renin-Angiotensin System (RAS) with the angiotensin-converting enzyme (ACE) and the angiotensin II AT1 receptor antagonist reduces the progression of kidney damage. The discovery of the angiotensin-converting enzyme 2 (ACE2) in the last decade has added a new level of complexity to the RAS pathway. ACE2 is found in various organs and is expressed abundantly in the kidney. Its main function is to break down the angiotensin I and II peptides. Previous studies have shown that in the glomeruli, ACE2 is mainly found on glomerular epithelial cells (podocytes) and in mesangial cells, while ACE is found on endothelial cells. In the diabetes type 2 experimental model, an imbalance was observed in the glomerular expression of ACE2/ACE in db/db mice, with reduced ACE2 expression and increased ACE expression.

We propose studying the expression of the intrarenal RAS in non-obese diabetic (NOD) mice, a diabetes model which is very similar to type I diabetic nephropathy in humans. In this way, we will analyse ACE and ACE2 renal expression in NOD diabetic mice. In addition, we will test to see if insulin administration is able to prevent the development of diabetic nephropathy and the effect this has on ACE/ACE2 renal expression in NOD diabetic mice.

Effect of insuline on ACE 2 expression in glomerular epithelial cell (podocyte) cultures.

It has been shown that ACE2 is present in the glomerular epithelial cells (podocytes) and mesangial cells in the kidneys of db/db diabetic mice. With the aim of broadening the aforementioned discoveries on the importance of ACE2 in the intrarenal renin-angiotensin aldosterone system (RAAS) in diabetic nephropathy, in this project we will focus on studying the RAAS between podocytes, a key cell in the development of albuminuria and diabetic nephropathy. We believe studying the effect of insulin on transcriptional and post-transcriptional ACE2 expression in podocytes will help us to clarify the effect hyperglycemia has on intrapodocyte RAS expression.

Effect of gender differences on diabetic Nephropathy in mice with ACE2 gene deletion.

Clinical and experimental studies suggest that there are gender differences in the incidence, prevalence and progression of chronic kidney disease. In this project, we will attempt to clarify if these differences are associated with changes in the Renin-Angiotensin System (RAS), focusing on studying mice with ACE2 gene deletion and diabetic mice following streptozotocin (STZ) administration. We will study the effect of gender differences on the kidney (urinary excretion of albumin and renal pathology) after using streptozotocin to induce diabetes in mice with ACE2 gene deletion.

In addition, we will study the effect of gender differences on oxidative stress and apoptosis. If the RAS is involved in the increased incidence and progression of chronic kidney diseases in men, strategies for inactivating the RAS will help to slow down disease progression.

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