The main focus of our research is to investigate the mechanism of development and progression of diabetic nephropathy (DN). Diabetes is prevalent in the people aged 20 years and older. The demographic of veterans population falls in this age group. In the US, diabetes represents the 6th leading cause of death; however, diabetes as a cause of death is underreported. Nearly 50% of the patients with diabetes develop nephropathy. A recent study demonstrated that diabetic patients with kidney disease had 87% higher risk of cardiovascular mortality when compared with those without kidney disease. The early pathologic changes in DN involve renal especially glomerular hypertrophy and expansion of matrix proteins such as collagen, fibronectin and laminin. My laboratory studies the signal transduction mechanisms that lead to the progression of DN. To test our concepts, we use both renal cells (glomerular mesangial and proximal tubular epithelial cells) in culture and mouse and rat models of diabetes. Since many pathologic effects of hyperglycemia are mediated by transforming growth factor-β (TGFβ), we investigate the signaling mechanisms of this cytokine in mesangial and proximal tubular epithelial cells. We discovered that the expression of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted in chromosome 10) is reduced in the diabetic kidney and in renal cells cultured in the presence of high glucose or TGFβ. In recent years, we have extensively investigated the mechanism of PTEN downregulation in renal cells and in kidneys of diabetic rodents. The results showed the involvement of TGFβ in high glucose-induced suppression of PTEN levels in renal cells. Our results for the first time demonstrated the role of microRNA (miR)-21, miR-26 and miR-214 in the inhibition of PTEN expression in the diabetic milieu. These studies opened the door to the novel application of anti-microRNA therapy for DN. More recently, we extended these studies to include the role of mTOR (mechanistic target of rapamycin) complexes 1 and 2 in diabetic kidney disease. We provided the first evidence for the requirement of inactivation of the exclusive PRAS40 subunit of mTOR complex 1 for glomerular mesangial cell hypertrophy, a pathologic feature of DN. Together with other VA investigators, we showed that rapamycin ameliorated the renal pathologies in diabetic mice. However, rapamycin-mediated complete inhibition of mTOR activity may cause deleterious clinical outcome. In fact, loss of mTORC1 in proximal tubular epithelial cells of mice induces progressive fibrosis. Therefore, more recently we have focused on a novel protein, called deptor, which is a component of both mTOR complexes 1 and 2. In fact, deptor is an endogenous inhibitor of mTOR activity. For the first time, we showed that the renal expression of deptor was significantly reduced in humans with diabetes and in diabetic rodents and that this reduction contributed to the increased mTOR activity. In cultured mesangial and proximal tubular epithelial cells incubated with high glucose, the expression of deptor was significantly reduced, which resulted in sustained activation of both mTORC1 and mTORC2. Thus, it is important to study the mechanisms of deptor downregulation by hyperglycemia. We are currently investigating the epigenetic, post-transcriptional and post-translational mechanisms of deptor reduction in diabetic kidney disease. Furthermore, recent studies have demonstrated a strong correlation between diabetes and renal cell carcinoma (RCC). Also, the incidence of RCC increases after 30 years of age and peaks at the 6th decades, which fall in the demographic of veterans population. We showed that downregulation of PTEN by increased expression of specific microRNAs contributes to the proliferation and invasion of renal carcinoma cells. Thus, the goal of our studies is to investigate the molecular mechanisms of the progression of diabetic nephropathy and RCC, and identify signaling molecules that can be targeted by small molecular drugs and anti-microRNA based therapies.

A recent study showed that nearly half of the hospitalized veterans had chronic kidney disease. Diabetes is one of the most prevalent chronic diseases among people aged 20 years and older in the US. Nearly 27% of people in the age group of 65 years or older, that falls in the demographics of veteran population, have diabetes with men and women in equal proportions. Diabetic nephropathy is the leading cause of end stage renal disease (ESRD), accounting for 44% new cases each year. Also, diabetes acts as a risk factor for renal cancer, the incidence of which increases from age 30 and peaks at 6th decade. Current therapies only delay the progression of diseases and do not arrest them. Thus there is an urgent need for therapeutic approaches, which may include blocking mechanisms of injury. Our studies on novel signaling mechanisms that drive these diseases will help identifying drugs that can lead to alleviating the burden of diabetes-associated kidney disease and kidney cancer.