Abnormal cyst-lining cell proliferation causing relentless cyst growth is believed to underlie the progressive loss of renal function in ADPKD. Published work from our laboratory using orthologous models of PKD1 and PKD2 demonstrates that macrophages enter the kidney in abnormally high numbers and surround the tubules just prior to cyst initiation and progressively accumulate around growing cysts. Whole animal depletion of macrophages inhibits cyst-lining cell proliferation, slows cyst growth and improves renal function. Our preliminary RNAseq and qPCR data from both PC1 and PC2 null kidneys reveals 14-16 fold increased expression of the monocyte chemoattractant Mcp1 preceding cyst formation that is absent in non-ciliated PC1 or PC2 null kidneys. These results have led us to hypothesize that cilia transduce a stimulatory signal for Mcp1 expression that is normally suppressed by PC1 expression. Cells lacking functional PC1 would thus be predicted to express high levels of Mcp1 causing sustained macrophage accumulation. We have previously demonstrated that alternatively activated macrophages stimulate tubular cell proliferation. FACS, qPCR and proteomic data from macrophages isolated from polycystic kidneys demonstrates that they are predominately alternatively activated and express high levels of insulin-like growth factor 1 (Igf1). Igf1 is a major tubule cell proliferative factor that can act cooperatively with Egf, which is known to be upregulated in human and rodent ADPKD, to stimulate cell proliferation in epithelia. Our goal is to define the pathways that are specific to PKD- dependent monocyte homing/macrophage activation and subsequent cyst growth in order to selectively interrupt those events and slow cyst growth without preventing normal macrophage or tubular function. The approach that we have chosen is designed to also define key regulatory steps in those pathways that can be therapeutically targeted to prevent this pathologic response. To achieve this we will first identify the source of exaggerated Mcp1 expression in ADPKD and use in vitro and in vivo interruption of that signal(s) to prevent macrophage homing to cystic kidneys (SA 1). We will then define the cellular mechanism by which PC1 null cilia induce Mcp1 expression and determine how polycystins normally suppress that signal(s)(SA 2). Finally, we will identify the role of macrophage-secreted Igf1, either alone or in concert with locally expressed Egf, in promoting PC1 null tubular cell proliferation in vitro and use in vivo interruption of Igf1 signaling to determine the therapeutic utility of targeting ths pathway for slowing cyst growth (SA 3).
In patients with Polycystic Kidney Disease, growth of the cysts causes slow, progressive loss of kidney function. We have found that macrophages enter cystic kidneys and stimulate more rapid cyst growth. This proposal will seek to find ways to block this response, slow cyst growth and preserve kidney function.
| Cassini, Marcelo F; Kakade, Vijayakumar R; Kurtz, Elizabeth et al. (2018) Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 29:2471-2481 |
| Huen, Sarah C; Cantley, Lloyd G (2015) Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol 30:199-209 |
