Upregulation of podocyte-secreted angiopoietin-like-4 in diabetic nephropathy

Abstract

Podocyte injury plays a key role in the development of diabetic nephropathy (DN). Understanding the changes in podocyte structure and function in diabetes mellitus may lead to novel diagnostic tools and treatment strategies for DN. Albuminuria, histological alterations, and podocyte injury were detected at different time points in streptozotocin (STZ)-induced diabetic rats. Increased urinary albumin-to-creatinine ratios (ACR) and podocyte injury were significantly observed 4 weeks post-STZ injection. We determined the glomerular expression and distribution of angiopoietin-like 4 (Angptl4) by immunofluorescence and real-time PCR. Glomerular Angptl4 expression was mostly colocalized with synaptopodin, a podocyte marker, with substantial additional overlap with the glomerular basement membrane (GBM). This finding indicated that Angptl4 might be primarily secreted by podocytes and moved toward the GBM. Moreover, we observed by Western blot analysis and ELISA that the urinary Angptl4 level was gradually upregulated in both STZ-induced rats and diabetic patients with microalbuminuria and macroalbuminuria. We further found that the increased glomerular Angptl4 expression was closely related to the urinary ACR level and podocyte injury. In addition, the urinary Angptl4 expression was closely associated with albuminuria in the rats and patients with DN. This study is the first to show that podocyte-secreted Angptl4 is upregulated in DN and can be detected in urine. Angptl4 might function as a podocyte injury marker and could be a potential and novel diagnostic and therapeutic biomarker for DN.

Circulating Permeability Factors in Idiopathic Nephrotic Syndrome

“…Rats overexpressing angptl-4 outside the kidney have high circulating levels of this factor but do not develop proteinuria, however, mice with podocyte overexpression of angptl-4 have normal circulating levels of the protein and do develop proteinuria 100) . Glomerular angptl-4 expression and urinary angptl-4 levels also increased in diabetic rats 101) . In healthy individuals, angptl-4 is minimally expressed in the glomeruli, but is upregulated in the serum and urine of MCD patients 102) .…”

Knockdown of ANGPTL-4 inhibits inflammatory response and extracellular matrix accumulation in glomerular mesangial cells cultured under high glucose condition

“…Thus, we could conclude that ANGPTL-4 participates in the development of diabetes. It has been observed that urinary ANGPTL-4 level is gradually upregulated in both streptozotocin (STZ)-induced diabetic rats and diabetic patients with microalbuminuria and macroalbuminuria [13]. They also proved that the urinary ANGPTL-4 expression is closely associated with albuminuria in the rats and patients with DN, indicating that ANGPTL-4 might be a potential diagnostic and therapeutic biomarker for DN.…”

Alteration of Angiopoietin-Like Protein 4 Levels in Serum or Urine Correlate with Different Biochemical Markers in Hyperlipidemia-Related Proteinuria

“…In 2015, Ma et al [23] revealed for the first time that high ANGPTL4 expression in the glomerular tissue was detectable in urine, and the ANGPTL4 in urine was secreted by podocytes, regardless of ANGPTL4 levels in the blood. The unique form of ANGPTL4 secreted by podocytes is incapable of entering the blood circulation.…”