Research Overview

Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological entity that is characterized by collapsing variant of focal segmental glomerulosclerosis and microcystic dilatation of tubules. It is predominantly a disease of young African American men.  Drug abuse has been considered a risk factor for the development of HIVAN.  The long-term goal of our research is to understand and develop strategies to modulate the progression of HIVAN.  In addition, we found that HIV-1 protein, Nef, stimulated expression of angiotensinogen in podocytes. Based on these results, we propose that HIV-1 infection leads to the activation of RAAS which can be further enhanced by usage of drugs. We are carrying out research to evaluate the effect of RAAS and drugs on HIVAN pathogenesis and to determine the molecular mechanisms involved in disease progression.  The outcome of these studies will help in the development of therapeutic strategies to treat this devastating renal disease. In addition, we are evaluating the involved mechanism of HIV-1 entry both in tubular and glomerular cells. We are also evaluating the role of immune mediated strategies to modulate the course of the progression of renal lesions in HIVAN.

Role of Renin-angiotensin-aldosterone in the development of HIVAN

Studies have shown that inhibition of the production and/or action of one of the components of renin-angiotensin-aldosterone system (RAAS) - Ang II, slows the progression of HIVAN. Interestingly, inhibition of action of other components of RAAS-renin and aldosterone, have also been demonstrated to retard the progression of renal lesions in other models of renal diseases. We hypothesize that inhibition of both renin and aldosterone either alone or in combination with Ang II blockade will provide better outcome in terms of providing protection against the progression of HIVAN. Preliminary data in our laboratory this notion. We intend to confirm these findings and carry out clinical trials in patients with HIVAN

Role of drugs in the development of renal lesions

Preliminary studies in our laboratory indicate that drugs such as morphine induce renal cell injury both in vivo and in vitro. These observations are consistent with a recent report indicating mice receiving morphine developed mesangial cell proliferation and glomerulomegaly after a short course therapy. These findings indicate that drugs have potential to contribute to renal lesions in HIV patients. We also noted that both losartan (an Ang II receptor blocker) and captopril (an agent which blocks the production of Ang II) inhibited morphine-induced renal cell injury (tubular cells and glomerular epithelial cells). Moreover, morphine stimulated production of angiotensinogen (a precursor of Ang II) by renal cells. We plan to evaluate the role of Ang II in drug-induced renal lesions in HIV-1 milieu.

Role of oxidative stress in the development of renal lesions in HIV-1 infection

Our recent preliminary studies in Tg26 (a mouse model of HIVAN) animals have shown that both glomerular and tubular cells showed enhanced generation of reactive oxygen species (ROS). In addition, in in vitro studies, podocytes-transduced with HIV-1 not only showed enhanced expression of p66ShcA but also demonstrated increased generation of ROS; whereas, p66ShcA-deficient podocytes showed attenuated generation of ROS. Interestingly, HIV-1 promoted human podocyte apoptosis which could be prevented by treatment with antioxidants as well as by inducing p66ShcA deficiency.   Based on these results we hypothesize that HIV-1 infection in conjunction with Ang II induces oxidative stress in glomerular and tubular epithelial cells which promotes the phosphorylation of p66shcA (Ser-36) and Akt; the latter  promotes the activation of mTOR and or Foxo3a  pathway(s) which contribute to the phenotypic alterations seen in HIVAN. We intend to prove  this hypothesis by elucidating the effect of p66ShcA expression and deficient states on HIVAN pathogenesis and to develop therapeutic strategies to prevent the disease progression.

HIV-1 entry into kidney cells

For a long time it was not clear whether the pathogenesis of HIVAN was due to HIV infection in the renal cell or due to an indirect effect of the systemically dysregulated immune system.  Studies designed to address this issue have shown that expression of the HIV-transgene in renal cells was necessary and sufficient for the development of HIVAN. In addition, increasing evidence supports a role for HIV-1 infection of renal epithelium in the pathogenesis of HIVAN. Recently, we demonstrated that HIV-1 enters into tubular cell via DEC-205 receptors. We are now investing the involved HIV-1 entry mechanism in podocytes.