Recent advances of animal model of focal segmental glomerulosclerosis

Abstract

In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

Ion-Channel modulator TH1177 reduces glomerular injury and serum creatinine in chronic mesangial proliferative disease in rats

“…Thy1 nephritis is a useful mechanistic tool for understanding the processes involved in MC injury and proliferative response in vivo, but it is far from analogous to the human diseases that we seek to modify, such as IgA nephropathy. Acute Thy1 nephritis is largely selflimiting with the injury resolving over 3-4 weeks [6]. More relevant is the development of chronic mesangial proliferative disease models using anti-Thy1 antibody injection after rat unilateral nephrectomy [7].…”

Mechanisms of Scarring in Focal Segmental Glomerulosclerosis

“…Classical animal models for FSGS rely on either direct or indirect induction of podocyte injury through the use of renal ablation, podocyte-specific toxins (adriamycin, puromycin aminonucleoside), or targeted genetic mutations (NEP25, diphtheria toxin [DT] receptor, or Thy-1.1 transgenic models). 3 As an example, the transgenic mouse strain NEP25 has been engineered to express the human CD25 receptor exclusively on podocytes. LMB2 is an immunotoxin that selectively targets human CD25.…”

“…Often, the genes that are manipulated in these models (e.g., ACTN4 , NPHS2, WT1, CD2AP ) have been identified by familial genetic studies as potentially playing a role in FSGS pathophysiology. 3…”

“…Often, the genes that are manipulated in these models (e.g., ACTN4, NPHS2, WT1, CD2AP) have been identified by familial genetic studies as potentially playing a role in FSGS pathophysiology. 3 Familial FSGS has been linked to a number of different genetic mutations, most of which encode for proteins that facilitate podocyte cytoskeleton dynamics, slit diaphragm integrity, and cellular signaling. 5 NPHS1 and NPHS2 encode for nephrin and podocin, respectively.…”

Adriamycin does not damage podocytes of zebrafish larvae

“…In order to induce glomerular injury in animal models, adriamycin (ADR or Doxorubicin) is widely used. ADR is an anthracycline that is commonly utilized to induce FSGS in rodents [11][12][13]. The efficacy of ADR is strongly dependent on the rodent strain it is used on.…”