Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

Abstract

The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3 -/-mice, which model Alport syndrome. Ablation of Usag1 in Col4a3 -/-mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3 -/-mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.

Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis

“…Third, the crosstalk between tubules and the glomerulus could be postulated. 38,39 Glomerulosclerosis secondary to proximal tubule injuries is also observed in clinical situations. Mesoamerican nephropathy 40 represents interstitial fibrosis and glomerulosclerosis after repeated episodes of AKI.…”

Defining cell-type specificity at the transcriptional level in human disease

“…PCOLCE2 protein modulates binding of procollagen C-proteases to collagen in a BMP1-dependent and celllineage-restricted manner (Steiglitz et al 2002), a process with significant relevance for the development and function of the glomerular basement membrane (Tanaka et al 2010). We investigated the disease-specific transcriptional regulation of PCOLCE2.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…A large number of therapeutic options to interfere with TGF-bioactivity has been tested in preclinical studies including antagonistic antibodies, soluble receptor forms, agents that inhibit downstream intracellular signaling molecules (in particular Smads), RNA interference and targeting of TGF--induced micro-RNAs (20,255,(257)(258)(259)(260). Other antifibrotic interventions in the system are focused on modulators of TGF-bioactivity, such as BMP-7 or BMP antagonists such as USAG-1 (253,261,262). BMP7 receptor Alk3 (263), and its downstream mediator Trps1 (264), have also been shown to be involved in kidney fibrosis.…”