Abstract
Podocyte loss and changes to the complex morphology are major causes of chronic kidney disease (CKD). As the incidence is continuously increasing over the last decades without sufficient treatment, it is important to find predicting biomarkers. Therefore, we measured urinary mRNA levels of podocyte genes NPHS1, NPHS2, PODXL and BDNF, KIM‐1, CTSL by qRT‐PCR of 120 CKD patients. We showed a strong correlation between BDNF and the kidney injury marker KIM‐1, which were also correlated with NPHS1, suggesting podocytes as a contributing source. In human biopsies, BDNF was localized in the cell body and major processes of podocytes. In glomeruli of diabetic nephropathy patients, we found a strong BDNF signal in the remaining podocytes. An inhibition of the BDNF receptor TrkB resulted in enhanced podocyte dedifferentiation. The knockdown of the orthologue resulted in pericardial oedema formation and lowered viability of zebrafish larvae. We found an enlarged Bowman's space, dilated glomerular capillaries, podocyte loss and an impaired glomerular filtration. We demonstrated that BDNF is essential for glomerular development, morphology and function and the expression of BDNF and KIM‐1 is highly correlated in urine cells of CKD patients. Therefore, BDNF mRNA in urine cells could serve as a potential CKD biomarker.
Highlights
The “Greifswald Approach to Individualized Medicine (GANI_MED)” aims at the development of individualized diagnosis, prevention and therapy strategies for common diseases.[1,2] patient cohorts were recruited and investigated under standardized and routine conditions
As the actin cytoskeleton plays an important role for podocyte morphology and adhesion in vivo, and podocyte detachment is a major event in glomerulopathies, we investigated the expression of brain-derived neurotrophic factor (BDNF) in cells appearing in the urine of patients suffering from chronic kidney disease (CKD) in an attempt to find out whether BDNF could be a suitable marker for the detection of diabetic nephropathy (DN)
Our study shows that the mRNA expressions of BDNF, a newly identified podocyte gene, and of kidney injury molecule‐1 (KIM-1), an injury‐induced protein, are highly correlated in urine cells of CKD patients and secondly that the expression is associated with DN
Summary
The “Greifswald Approach to Individualized Medicine (GANI_MED)” aims at the development of individualized diagnosis, prevention and therapy strategies for common diseases.[1,2] patient cohorts were recruited and investigated under standardized and routine conditions. As podocytes share certain structural and molecular biological characteristics with neurons, proteins involved in neuronal structural and physiological maintenance[11,12] are of great interest for podocyte research and might play a potential role as biomarkers. It has already been shown that BDNF binds to 2 different receptors—TrkB and p75, that are involved in cell survival and differentiation processes.[19,20] Recently, it has been reported that BDNF and TrkB are expressed in podocytes in vivo, being essential for actin polymerization and cell survival.[21] As the actin cytoskeleton plays an important role for podocyte morphology and adhesion in vivo, and podocyte detachment is a major event in glomerulopathies, we investigated the expression of BDNF in cells appearing in the urine of patients suffering from CKD in an attempt to find out whether BDNF could be a suitable marker for the detection of DN. We show the importance of BDNF for glomerular function in zebrafish larvae and in isolated murine glomeruli
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