Research Interest

Our research interests include the signal transduction pathways activated by growth factors, cytokines and hyperglycemic conditions. We are interested in mechanisms that support development of mesangioproliferative glomerulonephritis and diabetic kidney disease. Focusing on PDGF, which induces one of the most prevalent signaling pathways in humans, we are studying how PDGF induces the pathologic transformation of glomerular mesangial cells during  the  progression  of glomerulonephritis

During inflammatory state PDGF is secreted by the macrophages and by the resident mesangial cells. Activation of the PDGFR results in its tyrosine phosphorylation that initiates the signal transduction pathway. We have established that PDGF receptor mediated activation of PI 3 kinase and Akt contributes to the proliferation and migration of mesangial cells, two pathologic features of glomerulonephritis. We have identified the target genes downstream of this signaling pathway that regulates these pathological processes. We discovered that the tumor suppressor protein PTEN  associates  with PDGF receptor and dephosphorylates activated receptor. Thus PTEN  prevents PDGF receptor activation. This work provides a mechanism how mesangial cells are protected from PDGF-mediated conversion to proliferative and migratory cells in the disease state

.Recently, we are studying the role of mTOR and PTEN in pathology of a syndrome called tuberous sclerosis complex (TSC) that arises from mutation of TSC1/2 genes. We showed that renal angiomyolipomas from TSC  patients  exhibit  increased PTEN levels. Using embryonic fibroblasts from TSC2 null mouse and renal angiomyolipma tumor samples, we dissected the signaling sequence  that  regulates PTEN transcription via mTORC1 and mTORC2 dependent Hif1α transcription factor

Renal cell pathology in diabetic kidney disease and renal cancer

Working with cultured renal cells and mouse models of diabetes, we recently discovered that hyperglycemia and TGFβ reduce the expression of PTEN to regulate PI 3 kinase/Akt signaling pathway that is necessary for renal cell hypertrophy and matrix protein expression, two pathologic features of diabetic nephropathy. Recently, we turned our attention to involvement of microRNAs (miRs) in complications  of  diabetic nephropathy in type 1 diabetic mouse and in cultured renal glomerular mesangial and proximal tubular cells. We discovered a cross-talk between miR-21 and mTOR activation involving PTEN in these cells in response to high glucose and in diabetic mouse kidney. We also found the involvement of TGFβ in increasing miR-21 that regulates renal cell hypertrophy and matrix protein expression. Furthermore, our work show that upregulated miR-21 in clear cell renal tumors and in  cultured  renal  cancer  cells  regulates  PTEN levels post-transcriptionally to induce proliferation and invasion. These results suggest that common mechanisms exist between diabetic renal complications and renal carcinogenesis.
More  recently,  we  are  investigating  the  role  of  deptor,  an  mTOR  interacting protein, in the development of nephropathy using models of type 1 and type 2 diabetes. Our  recent  studies  show  that  TGFβ-induced  downregulation  of  deptor  contributes  to renal cell hypertrophy and Hif1α activation to  increase  transcription  of  matrix  protein gene fibronectin. Our current interest is directed to investigate the mechanisms of deptor regulation that contribute to renal cell pathology found in diabetic nephropathy. Our goal is to use this knowledge to prevent the complications associated with diabetic kidney disease