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Gary Désir, MD

Vice Provost for Faculty Development and Diversity; Chair, Department of Internal Medicine; and Paul B. Beeson Professor of Medicine; Affiliated Faculty, Yale Institute for Global Health

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Gary Désir, MD

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Research Summary

Discovery and naming of renalase (RNLS): a novel protein that regulates cell growth and survival, modulates the immune system and has therapeutic relevance to type 1 diabetes, acute cellular and organ injury, and to cancer

Renalase is a novel renal hormone that was discovered in our laboratory. It is synthesized by the proximal tubule and secreted in plasma where it metabolizes catecholamines and signals via a receptor-mediated pathway to enhance cell survival. Renalase deficiency aggravates renal and cardiac ischemic injury, and administration of recombinant renalase protects against ischemic and toxic acute kidney injury (AKI) and myocardial necrosis. Single nucleotide polymorphisms of the renalase gene are associated with essential hypertension, stroke and type 1 diabetes. We are currently investigating the molecular mechanisms mediating the direct cellular protective effect of renalase, its utility as a therapeutic agent for ischemic and toxic AKI, and as a potential biomarker for AKI.

Identification and validation of therapeutic targets for the treatment of obesity and diabetes

Voltage-gated potassium (Kv) channels regulate cell membrane potential and control a variety of cellular processes including insulin secretion. We found that the voltage-gated channel Kv1.3 and its signaling cascade represented a novel, pathway that regulates body weight and peripheral glucose metabolism. Inhibitors of Kv1.3 could prove useful in the management of obesity and diabetes.

Specialized Terms: Hypertension; Diabetes, Acute kidney injury; Catecholamines metabolism; immune regulation

Extensive Research Description

CONTRIBUTION TO SCIENCE

1- Discovery and naming of renalase (RNLS): a novel protein that regulates cell growth and survival, modulates the immune system and has therapeutic relevance to type 1 diabetes, acute cellular and organ injury, and to cancer. (2001-present)

The development of chronic kidney disease is associated with such a remarkable propensity of developing cardiovascular complications that the yearly risk of death is the same for 25-year-old person with end-stage kidney as it is for one who is 80 years old but has normal kidney function. In 2001 I decided to focus my research efforts on investigating the mechanisms underlying this observation and hypothesized that the kidney was producing a yet to be discovered protein that was secreted in plasma and that modulated cardiovascular function. We employed molecular and computer modeling methods to identify an unknown protein I named renalase (RNLS). It is a flavin adenine dinucleotide–dependent (FAD-dependent) amine oxidase that is secreted into the blood by the kidney, that appeared to metabolize circulating catecholamines and NADH, and regulate blood pressure.

Intracellularly, RNLS functions as an enzyme that participates in the metabolism of NADH and NADPH, The secreted form of RNLS is a survival factor that protects against ischemic and toxic organ injury (heart, kidney, liver and pancreas) independently of its enzymatic function. And it does so by activating a receptor-mediated, pro-survival signaling cascade (MAPK, AKT and STAT3). We have identified the key region of the RNLS molecule that mediates its cyto-protective action and have used this information to show the plasma membrane calcium ATPase isoform, PMCA4b functions as a receptor for extracellular RNLS.

Recent insights into RNLS’ pathophysiology relate to its overexpression in select human cancers, where it signals through specific pathways to promote the survival of cancer cells. RNLS modulates the immune system to inhibit recognition of tumor antigens through a pathway that does not overlap with that of the known checkpoint proteins. Secreted RNLS may turn out to be the original checkpoint protein given that it is ~3 billion years old and highly conserved throughout evolution.

Our most recent work indicates that RNLS could serve as a prognostic marker, and inhibitors of the RNLS pathway will be first-in-class therapeutics for the treatment of melanoma, pancreatic, breast and lung cancer. I am an inventor on several issued patents related to discovery and use of RNLS and the scientific inventor of 2 biotech companies.

2- Molecular physiology of voltage-gated potassium channels 1992-2006

a- Molecular identity of potassium (K) channels in kidney: voltage-gated K channels (1992)

A variety of potassium (K) channels had been detected in the mammalian kidney using electrophysiological methods. Although the physiological roles of some of these channels were unclear at the time, voltage-gated K (Kv) channels were postulated to participate in at least two important processes, K recycling and K secretion. The structure of renal K channels were not known at the time, and there was great interest in identifying genes encoding these channels.

The first member of the Shaker gene family (encodes Kv channels) had recently been identified using a mutant fly called Shaker. Although Shaker gene expression was believed to be restricted to excitable cells, and Shaker-like currents had not been detected by electrophysiological methods, we hypothesized that renal tubular cells involved in ion transport should experience changes in membrane voltage that are substantial enough to activate Kv channels. Therefore, we used PCR and degenerate oligonucleotides based on conserved Shaker sequences to probe for the expression of Shaker-like genes in rabbit kidney and the pig renal epithelial cell line LLC-PK1. These studies led to the identification of several Shaker related genes in mammalian. This was the first demonstration that Shaker-like genes were expressed in any epithelial cell. We subsequently showed that Kv1.1 was highly expressed in the distal tubule.

Subsequent to our work, genetics studies in families with hereditary forms of renal magnesium wasting have established that Kv1.1 is a key palyer in renal magnesium handling. Work carried out by the laboratory of Rene Bindels has provided convincing evidence that Kv1.1 maintains an inside negative membrane potential that drives magnesium entry via the transient receptor potential channel TRPM6 into renal distal tubular cell.

b- Identification of a new class of cyclic GMP-activated K channel (1995)

The molecular structures of Kv, calcium-activated (Kca), and ATP-regulated (Katp) potassium channels had been elucidated, and there was considerable interest in determining the structure of nucleotide-activated (Knuc) K channels since they were thought to play important roles in the maintenance of arterial tone and in the process of insulin secretion. The molecular structure of a class of ion channels that were gated by cyclic nucleotides but do not discriminate between sodium and potassium (nonselective cation channels) was known. They all contain a cyclic nucleotide binding region located at the C terminus. Sequence analysis indicates that these channels were distantly related to voltage-gated Shaker K channels.

Based on these data and on the fact that cyclic nucleotides were known to regulate renal K-channel activity we hypothesized that Knuc might share structural motifs with both Shaker K channels and cyclic nucleotide-gated cation channels. We used degenerate primers for the conserved Shaker regions and the cGMP binding domains to identify a novel member of the K channel gene family (Kcn1 or KCNA10) expressed in kidney and encoding a K-selective channel that is specifically activated by cGMP. This protein defines a class of K channels that has structural features common to voltage-gated Shaker-like K channels and to cyclic nucleotide-gated nonselective cation channels.

c- Cloning of KCNK1, the first two-pore K channel identified in man (1997)

It was clear that potassium channels exhibited great functional and structural diversity, and four major structural classes encoding a-subunits with two, four, six, or eight trans-membrane segments (TM) were known at the time. The 2-TM and 6-TM structural classes had been extensively studied in mammals and shown to consist of families, which were themselves divided into subfamilies made up of many members. In contrast to the 2-TM and 6-TM classes, which have been well characterized in many species including mammals, virtually nothing was known about the 4-TM and 8-TM classes of K channels. Data from the C. elegans genome sequencing project suggested that the 4-TM class of K channels contains at least 23 different genes.

These channels display the unusual structural feature of having two putative pore regions in contrast to all previously cloned K channels (2-TM and 6-TM), which only have one pore. The first member (TOK1) of the 8-TM class, had recently been identified in yeast, had two pore domains and encoded an outward-rectifying K channel. A 4-TM K channel cloned from Drosophila also had two pores and mediated K currents with outward rectification dependent on external K concentration.

We used computer modeling and database mining to identify mammalian sequences encoding putative double pore channels. This work resulted in the cloning and characterization of the first two-pore K channel (KCNK1) identified in man. We also showed that expression of KCNK1 in rabbit kidney was limited to the distal nephron. Fifteen two-pore channels have subsequently been identified in mammals, and they play key roles in cell and organ physiology, and are regulated by several mechanisms, including oxygen tension, pH, mechanical stretch and G-proteins.

d- The voltage-gated Kv1.3 channel regulates body weight and insulin sensitivity (2004)

Kv1.3 is a Shaker-related, voltage-gated potassium (Kv) channel expressed in many tissues. Examination of Kv1.3-deficient mice (Kv1.3 KO) generated by gene targeting, revealed a previously unrecognized role for Kv1.3 in body weight regulation. Kv1.3KO mice weigh less than control littermates and are protected from diet-induced obesity. Indeed, when maintained on a high-fat diet for up to 7 months, they gain less weight than control littermates. Most likely channel inhibition increased basal metabolic rate.

Interestingly, although Kv1.3 KO mice exposed to a high-fat diet become obese, they are euglycemic and have normal blood insulin levels. This observation, along with the fact that Kv1.3 activity is regulated by insulin in the olfactory bulb, prompted us to examine the effect of Kv1.3 gene inactivation and inhibition on peripheral glucose homeostasis and insulin sensitivity. We showed that Kv1.3 is an important component of the pathways that regulate glucose homeostasis. Inhibition of channel activity, either by gene deletion or by channel blockers, significantly increases peripheral insulin sensitivity by recruiting GLUT4 to the plasma membrane by down-regulating IL-6 and TNF secretion and JNK activity. The channel and its signaling pathway represent potential targets for the development of drugs useful in the management of diabetes. I am an inventor on an issued a patent covering compositions and methods relating inhibition of Kv1.3 to improve glucose metabolism, and control weight control and food intake (Patent number US 6,861,405 B2, USA 2005).

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Research Interests

Catecholamines; Diabetes Mellitus; Hypertension; Internal Medicine; Obesity; Acute Kidney Injury

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