The possible involvement of tensin2 in the expression and extension of nephrin by glomerular podocytes in mice

Abstract

The prevalence of chronic kidney disease (CKD) is increasing worldwide and proteinuria is a critical prognostic indicator of CKD. Nephrin is produced by podocytes and functions as a slit barrier for inhibition of proteinuria. Nephrin expression is frequently decreased in CKD patients. Nevertheless, the mechanism by which nephrin declines during CKD-related pathological states remains to be determined. Using tensin2-deficient mice (ICGN/Oa strain), we provide evidence that tensin2 is important for glomerular nephrin expression in vivo. In heterozygous mice with a single mutated tensin2 allele, nephrin expression was maintained, while albuminuria was not observed. In contrast, nephrin expression was impaired, especially in the central zones of glomeruli of homozygous mice (with double mutated tensin2 alleles), even at one week after birth. In homozygous mice, extension of synaptopodin, a key actin-associated protein, was also suppressed in the central zone of glomerular tufts. Consistent with the loss of nephrin and synaptopodin expression, severe albuminuria was detected in homozygous ICGN/Oa mice. Therefore, we suggested that tensin2 is involved in expression and extension of nephrin, while tensin2 deficiency may result in proteinuria, associated with the loss of slit integrity.

Decreases in Podocin, CD2-Associated Protein (CD2AP) and Tensin2 May Be Involved in Albuminuria during Septic Acute Renal Failure

“…Of interest, a loss of tensin2 acts as a switch to trigger cell migration [27]. Tensin2 localizes mainly to podocytes in the kidney [5,17], and notably, tensin2 homozygous mutation (i.e., tensin2-deficiency) in the mice (i.e., ICGN strain with an ICR background) leads to albuminuria within a few weeks after birth [5,17,24]. By contrast, there was no significant albuminuria in the congenic strain carrying the tensin2 mutation on the C57BL/6J genetic background [28], which raises a controversial issue about the role of tensin2 during albuminuria.…”

“…Using a model of an "acquired" kidney disease (i.e., septic ARF), we found the involvement of decreased tensin2 in septic albuminuria. Tensin2 is required for stability of synaptopodin [17]. In turn, synaptopodin is important for podocytes to sustain FP extension (i.e., podocyte outgrowth) [9,21,31].…”

“…We next focused on tensin2, a novel molecule that is required for stable expression of synaptopodin during congenital nephrotic syndrome in mice (ICGN strain) [17]. Tensin2 was detected in the extra-capillary areas (i.e., podocyte-localized area) of the saline-injected control mice (36 hr) (Fig.…”

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

“…In brief, > 30 glomeruli were randomly chosen, and the nephrin staining of each glomerulus was scored based on the extent of immunostaining in a whole tuft, as follows: 0 = none, 1 = faint, 2 = mild, 3 = moderate, 4 = strong (19,23). The individual value of nephrin staining intensity was expressed as the marker index, which was calculated using the following formula: marker expression index = (total score / glomerular number examined) (19,23).…”

“…The sections were incubated at 4°C for overnight, washed three times with phosphate buffered saline (PBS) and then subjected to a second reaction with biotin-conjugated anti-goat IgG (Vector, Burlingame, CA, USA). Finally, an avidin biotin coupling reaction was done on the sections, using an ABC kit (Elite ® : Vector) (19,23). All antigens were identified via visualization of horseradish peroxidase with 3,3'-diaminobenzidine (Nacalai, Kyoto, Japan).…”