Diabetic Nephropathy: Urinary loss of albumin and other proteins (= proteinuria) is an early characteristic of diabetic nephropathy. Proteinuria is presumed to result from increased passage of proteins through the glomerular filtration barrier as a consequence of raised transcapillary pressure as well as structural alterations. The glomerular filtration barrier consists of capillary endothelial cells, the glomerular basement membrane, and the so called podocytes (highly specialized epithelial cells). Importantly, morphological alterations of podocytes and finally podocyte loss resulting from apoptosis occur at the onset of diabetic nephropathy. Therefore, one main focus of our research group lies in the identification and molecular characterization of pro-apoptotic and anti-apoptotic factors determining podocyte biology and podocyte survival.
Recently we identified that podocyte survival and endoplasmic reticulum (ER) stress are regulated by free fatty acids (FFAs). Palmitic acid induces podocyte ER stress leading to an unfolded protein response (UPR) as reflected by the induction of the ER chaperon BiP and the proapoptotic transcription factor CHOP. Of note, we found that the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of BiP and CHOP, thereby completely preventing cell death. Similarly, we could demonstrate that gene silencing of CHOP protects against palmitic acid induced podocyte apoptosis. The clinical relevance of our results is underscored by the recently reported finding that CHOP-deficient mice are protected from diabetic nephropathy. Also in microdissected glomeruli from patients with diabetic nephropathy we observed that the gene expression of BiP is significantly upregulated further underscoring the relevance of ER-stress and UPR in the pathogenesis of diabetic nephropathy. Currently, we are investigating which molecular pathways determine and modulate the effects of FFAs. Additionally, we study whether other factors of the “diabetic milieu” critically impact the biology of podocytes.