Can we cure HIV-1-associated nephropathy in transgenic mice?
Authors: Patricio E. Ray
Journal: Kidney International (2012)

HIV-1–associated nephropathy (HIVAN) is a rapidly progressive form of focal segmental glomerulosclerosis. HIV transgenic mice can develop a HIVAN-like renal disease. Zhong et al. show that the oral administration of a cyclic nucleotide phosphodiesterase 4 inhibitor and a retinoic acid receptor-α agonist can prevent the development of HIVAN in transgenic mice, acting through a cAMP-dependent mechanism that is independent of HIV-1 genes. These findings suggest that endogenous host factors play a critical role in HIVAN. HIV-1–associated nephropathy (HIVAN) is a rapidly progressive form of focal segmental glomerulosclerosis. HIV transgenic mice can develop a HIVAN-like renal disease. Zhong et al. show that the oral administration of a cyclic nucleotide phosphodiesterase 4 inhibitor and a retinoic acid receptor-α agonist can prevent the development of HIVAN in transgenic mice, acting through a cAMP-dependent mechanism that is independent of HIV-1 genes. These findings suggest that endogenous host factors play a critical role in HIVAN. The late physician-scientist Dr Judah Folkman, considered by many to be the father of antiangiogenic cancer therapies, showed that certain types of experimental cancers in mice could be cured by disrupting their blood supply without directly attacking the tumor cells. His revolutionary treatment is currently being tested in patients with angiogenic tumors, including AIDS-associated Kaposi's sarcoma. Although the pathogenesis of HIV-1-associated nephropathy (HIVAN) is clearly different from that of AIDS-associated Kaposi's sarcoma, HIVAN is characterized by the excessive proliferation of renal glomerular and tubular epithelial cells, leading to the microcystic transformation of renal tubules and rapid development of focal segmental glomerulosclerosis. Therefore, the new study by Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar (this issue) challenges us to ask a similar type of question: Can we cure HIVAN in transgenic (Tg) mice without attacking the HIV-1 genes? Briefly, the study by Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar shows that the oral administration of two drugs that increase the intracellular levels of cyclic adenosine monophosphate (cAMP), roflumilast and Am580, is capable of curing HIVAN in Tg mice without affecting the expression of HIV-1 genes. Roflumilast is a cyclic nucleotide phosphodiesterase 4 (PDE4) inhibitor that increases the intracellular concentration of cAMP by blocking its degradation. Am580 is a specific retinoic acid receptor-α (RARα) agonist that has several systemic and renal effects, including increasing the intracellular levels of cAMP. Both drugs, acting in a synergistic manner, prevented the progression of the renal disease in HIV-Tg mice by blocking the dedifferentiation and proliferation of podocytes through a cAMP/protein kinase A/CREB-dependent pathway1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar (Figure 1). This pathway requires the participation of RARα in the nucleus of podocytes, in addition to the direct activation of cAMP and protein kinase A in the cytoplasm of these cells. The mechanism by which retinoic acid receptor agonists induce a direct activation of cAMP in the cytoplasm is not well understood, but similar findings have been documented in acute myeloblastic leukemia cells.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar However, Am580 did not prevent the progression of HIVAN in dual HIV-Tg/RARα knockout mice,2.Ratnam K.K. Feng X. Chuan P.Y. et al.Role of the retinoic acid receptor-α in HIV-associated nephropathy.Kidney Int. 2011; 9: 624-634Abstract Full Text Full Text PDF Scopus (58) Google Scholar suggesting that the nuclear RARα plays a key role in this process. Thus, more studies are needed to determine how RARα may induce the rapid activation of cAMP in the cytoplasm, and to validate this pathway in normal human podocytes. Finally, Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar conclude that the beneficial effects of roflumilast and Am580 were independent of HIV viral genes. Overall, these provocative findings raise several interesting issues that need to be discussed. First, Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar used a new colony of HIV-Tg mice that was re-derived from the parent HIV-Tg26 mouse line. Therefore, to understand how HIVAN can be cured in these mice, it is necessary to review the natural history of renal disease in Tg26 mice. Briefly, these mice carry a replication-deficient Δ gag/pol PNL4-3 HIV proviral genomic DNA driven by the endogenous HIV-1 promoter.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar The mRNA expression of HIV-1 is detected in a wide range of cells, including glomerular and tubular epithelial cells.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar, 4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar, 5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Viral proteins cannot, however, be detected in the circulation or peripheral blood mononuclear cells. Heterozygous mice are born with normal kidneys but develop progressive renal disease during their first months of life.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar Usually, male mice develop a more rapid and progressive renal disease when compared with female mice.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar, 4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar, 5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Severe edema and nephrotic syndrome occur approximately between 60 and 250 days of age.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar, 4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar, 5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Tg26 mice usually show blood urea nitrogen (BUN) levels exceeding 200mg/dl and elevated serum creatinine (>1mg/dl) in this time period and die of uremia and ascites.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar However, not all mice develop renal disease, and others do it in an asynchronous and unpredictable manner.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar, 4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar, 5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Thus, a remarkable finding of the study of Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar is that all untreated control HIV-Tg mice, both males and females, developed chronic renal failure in a synchronized manner during the first 9 weeks of life. Moreover, the prevalence of the renal disease in the control group was increased relative to that in the parent Tg26 mouse line,3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar and to the expected prevalence (∼80%) in the re-derived mouse colony. We should consider that Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar preselected mice at 4 weeks of age on the basis of urine dipstick protein values of 1+/2+ (30–100mg/dl). However, similar levels of proteinuria can be detected in Tg26 mice without renal disease,3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar due to the normal excretion of low-molecular weight tubular proteins and pheromones. In summary, one limitation of the study by Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar is that we do not know how many mice in each group had preexisting renal disease at the beginning of the study. Another limitation of this study is the definition of chronic renal failure: BUN levels greater than 30mg/dl. Previous publications on Tg26 mice reported similar BUN levels in mice without renal disease and used cutoff BUN values above 45mg/dl.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar These BUN values revealed a much better correlation with the renal histological findings associated with chronic renal failure, showing all glomeruli with segmental or global glomerulosclerosis in combination with microcystic tubular dilatation.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar In contrast, 30–40% of the mice treated with roflumilast or Am580 alone were reported as having chronic renal failure but showed only ‘mild’ glomerular sclerotic changes, very few collapsed glomeruli, and mild tubulointerstitial injury scores. The data presented by Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar also appear to exclude the possibility that these mice suffered weight loss, or prerenal failure secondary to drug-induced diarrhea, dehydration, severe edema, nephrotic syndrome, or ascites. Thus, it is unclear why these mice developed chronic renal failure with such renal histological and clinical findings. Moreover, a previous study by the same group showed that a more prolonged treatment with Am580 alone was capable of preventing the progression of HIVAN in Tg26 mice.2.Ratnam K.K. Feng X. Chuan P.Y. et al.Role of the retinoic acid receptor-α in HIV-associated nephropathy.Kidney Int. 2011; 9: 624-634Abstract Full Text Full Text PDF Scopus (58) Google Scholar Finally, for the purpose of comparing the outcome of the renal disease in mice belonging to the original Tg26 line3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar versus those used in this study,1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar both the renal histological and clinical findings at 9 weeks of age appear to be more severe in Tg26 mice.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar, 4.Kopp J.B. Klotman M.E. Adler S.H. et al.Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes.Proc Natl Acad Sci USA. 1992; 89: 1577-1581Crossref PubMed Scopus (281) Google Scholar, 5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Nevertheless, when the findings of Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar are considered in the context of previous studies,6.Wagner J. Potential role of retinoids in the therapy of renal disease.Nephrol Dial Transplant. 2001; 16: 441-444Crossref PubMed Scopus (19) Google Scholar, 7.Cheng J. Grande J.P. Cyclic nucleotide phosphodiesterase (PDE) inhibitors: novel therapeutic agents for progressive renal disease.Exp Biol Med. 2007; 232: 38-51PubMed Google Scholar, 8.Morath C. Dechow C. Lehrke I. et al.Effects of retinoids on the TGF-β system and extracellular matrix in experimental glomerulonephritis.J Am Soc Nephrol. 2001; 12: 2300-2309PubMed Google Scholar it is clear that roflumilast and Am580 have the potential to improve the outcome of HIVAN acting through different mechanisms and renal cell types (Figure 1). For example, Zhong et al.1.Zhong Y. Wu Y. Liu R. et al.Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.Kidney Int. 2012; 81: 856-864Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar began their treatment when mice were 4 weeks of age. Renal electron microscopy studies done in Tg26 mice with renal disease at this early time point show effacement of foot processes, expansion of the mesangial matrix, narrowing of the lumen of glomerular capillaries, simplification and atrophy of tubular epithelial cells, and thickening of glomerular and tubular basement membranes.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar No renal epithelial proliferative changes, however, are detected at this early stage.3.Dickie P. Felser J. Eckhaus M. et al.HIV-associated nephropathy in transgenic mice expressing HIV-1 genes.Virology. 1991; 185: 109-119Crossref PubMed Scopus (239) Google Scholar,5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Thus, in addition to the pro-differentiation changes in podocytes described by Zhong et al., these drugs have the potential to improve the outcome of HIVAN by blocking the synthesis and accumulation of renal extracellular matrix proteins. Previous studies suggest that these changes can be mediated by cAMP-dependent and/or transforming growth factor-β-dependent mechanisms.8.Morath C. Dechow C. Lehrke I. et al.Effects of retinoids on the TGF-β system and extracellular matrix in experimental glomerulonephritis.J Am Soc Nephrol. 2001; 12: 2300-2309PubMed Google Scholar,9.Duncan M.R. Frazier S.K. Abramson S. et al.Connective tissue growth factor mediates transforming growth factor β-induced collagen synthesis: down-regulation by cAMP.FASEB J. 1999; 13: 1774-1786Crossref PubMed Scopus (577) Google Scholar In addition, blocking the synthesis of heparan sulfate proteoglycans (Figure 1) may prevent the renal accumulation of heparin-binding growth factors, including vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor-2 (FGF-2), which can induce renal proliferative changes during the late stages of HIVAN in Tg26 mice.5.Ray P.E. Bruggeman L.A. Weeks B.S. et al.bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice.Kidney Int. 1994; 46: 759-772Abstract Full Text PDF PubMed Scopus (91) Google Scholar Moreover, previous studies showed that drugs that increase the intracellular levels of cAMP can also decrease the mitogenic activity of FGF-2 in cultured human primary renal epithelial cells by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway10.Izevbigie E.B. Gutkind J.S. Ray P.E. Isoproterenol inhibits fibroblast growth factor-2-induced growth of renal epithelial cells.Pediatr Nephrol. 2000; 14: 726-734Crossref PubMed Scopus (18) Google Scholar (Figure 1). In summary, it is tempting to speculate that retinoids, in combination with PDE4 inhibitors, may ameliorate the progression of HIVAN independently of HIV genes, by blocking the dedifferentiation of podocytes and the synthesis of extracellular matrix proteins during the early stages of the renal disease, and by preventing the mitogenic activity of heparin-binding growth factors during the late stages of HIVAN. Finally, roflumilast and Am580 have powerful systemic effects, which could also modulate the outcome of HIVAN in humans and Tg mice. For example, retinoids can decrease the blood pressure of mice with renal disease8.Morath C. Dechow C. Lehrke I. et al.Effects of retinoids on the TGF-β system and extracellular matrix in experimental glomerulonephritis.J Am Soc Nephrol. 2001; 12: 2300-2309PubMed Google Scholar and may improve their renal outcome by modulating the activity of nitric oxide synthase, endothelin-1, and/or angiotensin II type 1 receptors.6.Wagner J. Potential role of retinoids in the therapy of renal disease.Nephrol Dial Transplant. 2001; 16: 441-444Crossref PubMed Scopus (19) Google Scholar Most notably, these drugs have powerful anti-inflammatory activity and can affect the recruitment of inflammatory cells, as well as the transcription of inflammatory genes, acting through activator protein-1- or nuclear factor-κB-related mechanisms (Figure 1).6.Wagner J. Potential role of retinoids in the therapy of renal disease.Nephrol Dial Transplant. 2001; 16: 441-444Crossref PubMed Scopus (19) Google Scholar Roflumilast also inhibits the expression of the cytokine monocyte chemoattractant protein-1 and the generation of reactive oxygen species.7.Cheng J. Grande J.P. Cyclic nucleotide phosphodiesterase (PDE) inhibitors: novel therapeutic agents for progressive renal disease.Exp Biol Med. 2007; 232: 38-51PubMed Google Scholar On the basis of its anti-inflammatory activity, roflumilast was approved by the US Food and Drug Administration to treat flares of chronic obstructive pulmonary disease. Unfortunately, this drug cannot be used in patients with liver disease and has known adverse interactions with several HIV medications. Alternatively, retinoids are being used in clinical trials to treat skin lesions and tumors, including AIDS-associated Kaposi's sarcoma, and in patients with minimal-change disease or focal segmental glomerulosclerosis. Overall, we hope that these studies will provide valuable information to assess the clinical value of roflumilast and Am580 in patients with HIVAN. This work was supported in part by National Institutes of Health grants R01-HL55605, R01-DK049419, and R01-HL-102497.