Insulin‐like growth factor‐II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse

Abstract

Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro-survival mechanisms are critically important. Insulin-like growth factor-II (IGF-II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF-II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF-II; it signals to this cell via the IGF-I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF-II transgenic mouse that produces approximately 60% of IGF-II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF-II in the mature podocyte for glomerular health across mammalian species.

Insulin directly stimulates VEGF-A production in the glomerular podocyte

“…Previously, we (13,33) showed that insulin predominantly signals through the IR and that IGFs signal predominately through the IGF-IR in the podocyte. Therefore, we genetically induced insulin and IGF resistance in podocytes by knocking down the major receptors through which insulin and IGFs signal, the IR and IGF-IR.…”

“…Short hairpin (sh)RNA knockdown of the IR and IGF-IR was performed as previously reported (13,33). We studied two clones with similar levels of receptor knockdown in this report: 75% knockdown for the IR and 81% knockdown for the IGF-IR.…”

“…Cell survival was analyzed through inspection and the use of a MTS assay to monitor cell death as previously described (13).…”

“…We have shown that IGF-I and IGF-II signal predominantly through the IGF-IR and that these pathways are critically important for podocyte survival. When the receptor is stably knocked down in these cells, there is significant cell death as they mature (13).…”

“…Recently, we (13) have dissected out the role of IGF signaling in the podocyte. We have shown that IGF-I and IGF-II signal predominantly through the IGF-IR and that these pathways are critically important for podocyte survival.…”