Glomerular MYH9 expression is reduced by HIV-1

Abstract

The continuing disease burden of HIV-associated nephropathy (HIVAN) warrants better elucidation of its pathogenic mechanisms. Given that loss of MYH9 function causes a Mendelian renal disease, we hypothesized that renal expression of MYH9 is downregulated by HIV-1 in HIVAN pathogenesis. Using immunofluorescence, we determined that glomerular expression of MYH9 was reduced in the kidneys of HIV-1 transgenic mice. We further determined that Myh9 expression was reduced in HIV-1 transgenic podocytes, statistically significantly at the protein level, and that MYH9 expression was significantly reduced at protein and message level in human podocytes transduced with HIV-1. In analyzing expression in human tissue, we confirmed that MYH9 is abundantly expressed in glomeruli, and podocytes specifically. Finally, we found that MYH9 expression was significantly reduced in human glomeruli in the setting of HIVAN. We conclude that the podocyte host response to HIV-1 includes downregulation of MYH9 expression, and hypothesize that this downregulation might play a role in the pathogenesis of HIVAN.

Next-Generation Sequencing of Small RNAs from HIV-Infected Cells Identifies Phased microRNA Expression Patterns and Candidate Novel microRNAs Differentially Expressed upon Infection

“…Relieving the inhibition of these transcription factors via the suppression of miR-3607-3p and other microRNAs may represent an early event of HIV infection which is reversed later in HIV infection. Consistent with this interpretation, the MYH9 gene (myosin, heavy chain 9, nonmuscle), a target mRNA of miR-3607-3p found downregulated later in infection, was also found to be downregulated in HIV-infected human glomeruli, which may contribute to HIV-associated pathology (25). While we cannot discern the mechanism by which viral entry or internalization might suppress miR-3607-3p and other early DE microRNAs from our data, we speculate that a surface protein such as gp120 initiates a signaling cascade that destabilizes the available pool of miR-3607-3p.…”

MYH9 and APOL1 Gene Polymorphisms and the Risk of CKD in Patients with Lupus Nephritis from an Admixture Population

“…In animal studies, mutations in MYH9 are related to phenotypic kidney abnormalities including albuminuria and FSGS [27], [28], as well as defects in morphogenesis [29]. HIV-1 downregulates the expression of MYH9 in transgenic mice, a finding confirmed in humans [30]. In addition, MYH9 mutation is related to FSGS in the giant platelet syndromes, a clinical fact that suggests that this protein actually has a role in the podocyte biology.…”

Proteomics Analysis of the Non-Muscle Myosin Heavy Chain IIa-Enriched Actin-Myosin Complex Reveals Multiple Functions within the Podocyte

“…NMMHCIIA has previously been shown to be expressed in healthy human glomeruli, within podocytes specifically [11]. However, it’s subcellular localization has not been described.…”

“…Nef contains a Src homology 3 (SH3)-binding domain, which mediates Src kinase activation, and activation of Stat3 and MAPK1,2 pathways [51]–[53]. The role of nef in mediating podocytopathy, and previous demonstration that MYH9 is down-regulated by HIV-1 in the podocyte [11], indicates that MYH9 down-regulation is likely part of the same nef -mediated signaling cascade that includes RhoA down-regulation. The PPIs identified in this analysis could have important therapeutic implications for the treatment of nef -mediated pathogenesis in HIVAN, especially given the implications that loss of NMMHCIIA function mediates renal disease.…”

“…MYH9 SNPs independently associate with a risk of sickle cell nephropathy [10]. Additionally, glomerular expression of MYH9 is down-regulated by HIV-1 in HIVAN [11]. Finally, it has been shown that ablation of MYH9 in podocytes predisposes mice to adriamycin-induced nephropathy [12].…”