Pharmacologic Blockade of αvβ1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo

Abstract

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells is poorly understood. PDGF receptor (PDGFR) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR promoter-driven Cre system to delete v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR-Cre line to isolate and study renal fibroblasts We found that renal fibroblasts express threev integrins, namely v1, v3, and v5. Blockade of v1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-1 and prevented activation of the latent TGF- complex. Continuous administration of a recently described potent small molecule inhibitor of v1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of v1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

An integrin antagonist (MK‐0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model

“…Recently, an avb1 inhibitor, compound 8 (C8) has been shown to have anti-fibrotic properties in pulmonary and hepatic fibrosis models (Reed et al 2015). More recently, C8 was also shown to be protective in the UUO and adenine induced renal injury models (Chang et al 2017). Our data suggest that MK-0429-dependent inhibition of avb1 is partially responsible for the anti-fibrotic effects in vivo; however, it is likely that inhibition of avb6, avb8, and potentially a5b1 are also involved in this process.…”

“…More recently, C8 was also shown to be protective in the UUO and adenine induced renal injury models (Chang et al. ). Our data suggest that MK‐0429‐dependent inhibition of α v β 1 is partially responsible for the anti‐fibrotic effects in vivo; however, it is likely that inhibition of α v β 6, α v β 8, and potentially α 5 β 1 are also involved in this process.…”

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

“…Progressive fibrosis, moreover, leads to enhanced tissue stiffness. Loss of elasticity stimulates the conversion of latent to bioactive TGF-b1 as a result of integrin engagement and cellular force generation (51)(52)(53). This increasingly noncompliant TGF-b1-rich microenvironment promotes myofibroblastic differentiation while activating the Hippo pathway mechanosensitive effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), which in turn reinforce expression of genes encoding the profibrotic factors plasminogen activator Figure 1.…”

The Design of Potent, Selective and Drug‐Like RGD αvβ1 Small‐Molecule Inhibitors Derived from non‐RGD α4β1 Antagonists

“…Compound 1 showeda ni mpressive decrease in fibrosis in lung, liver,a nd kidney in vivo models, leading the authors (Reed et al) to state that "compoundsb ased on this lead compound could be broadly useful fort reatment of diseases characterizedb ye xcessive tissue fibrosis". [7] However,c ompound 1 has poor pharmacokinetic (PK) properties which makes in vivo investigation difficult. In addition, while 1 delivers exquisite avs electivity,i th as recently been shownt oh ave additional b1a ctivities,w hichm ay complicate furthert arget validation studies.…”

“…[a] Reportedd ata: avb1I C 50 0.089-0.63 nm. [7,18] [b] Reported data: a4b1 IC 50 0.46 nm. [19] [c] Reported data:T R-14035 a4b1I C 50 87 nm.…”