Ph.D. 1985, Medical College of Georgia
Specialty: Pathophysiology of Acute Ischemic Renal Injury
Major Interest: Cellular, biochemical and molecular approaches to study of acute renal injury
The major focus of the laboratory is to study the mechanisms of cellular injury in acute kidney injury (AKI) and renal fibrogenesis in chronic kidney disease (CKD) models. The mechanisms by which energy depletion occurs in the kidney proximal tubules, which is the primary cause of cellular injury and death after AKI are being investigated. A second area of interest is the molecular mechanisms that regulate different forms of cell death, including apoptosis, necrosis and autophagy in various experimental models of AKI. In both patients and experimental models, although normal or near normal kidney function is regained after an ischemic episode, significant risks of long term loss of renal function and development of renal fibrosis and progression to chronic kidney disease exists. We are currently studying the role of neural factors and epoxyeicosatrienoic acids (EETs) in the regulation of renal fibrogenesis in different models of CKD. In collaborative projects, the laboratory is developing 1) novel drug delivery approaches in AKI and CKD and 2) characterizing a novel mouse model of congenital obstructive nephropathy. Further details of the different projects that are currently underway are presented below.
PROJECT 1: REGULATION OF ENERGY METABOLISM IN AKI: Ischemic renal injury (IRI), generally accepted as the major cause of AKI, results from compromised perfusion of renal tissues. Our studies identified poly (ADP-ribose) Polymerase-1 (PARP-1) and Tp53 inducible glycolysis and apoptosis regulator (TIGAR) and p53 to be key molecules that may inhibit glycolysis and fatty acid oxidation (FAO) in renal proximal tubules. This project is aimed at understanding the molecular mechanisms by which these molecules participate in inhibition of glycolysis and FAO and to determine if intervening in their functions may modulate tubular injury and the pathogenesis of AKI.
PROJECT 2: PROGRAMMED NECROSIS IN AKI: Necrotic cell death is widely considered to be an unregulated process that cannot be modulated by pharmacological means as opposed to apoptosis. However, our recent studies using experimental models of AKI challenge this tenet and indicate that necrosis can be “programmed” and can be prevented by targeting the molecular components of its signaling pathways, such as the mitochondrial pore forming protein, cyclophilin D (cypD) and the nuclear DNA repair enzyme Poly (ADP)-ribose polymerase (PARP). Project 3 is aimed at addressing the mechanisms by which Ca2+, PARP-1 and cyclophilin D contribute to mitochondrial dysfunction and mitochondrial permeability to ensue necrosis in ischemic and nephrotoxic (cisplatin) kidneys.
PROJECT 3: NEUROREGULATION OF RENAL FIBROGENESIS: Chronic kidney disease (CKD) is progressive, not curable, and ultimately fatal. Regardless of the disease etiology, including hypertension, diabetes and glomerulonephritis, tubulointerstitial fibrosis is the final common pathway in CKD that leads to disease progression and ultimately end stage renal disease (ESRD). Our results suggest that afferent and efferent renal nerve stimulation may be the primary mechanism and nerve derived factors play key role in the initiation of fibrogenesis and the inflammatory cascade in the kidney. Studies are in progress to understand the mechanisms by which renal innervation contribute to renal injury and chronic kidney disease.
PROJECT 4: NOVEL DRUG DELIVERY STRATEGIES IN AKI AND CKD: Polymer-based carriers have strong potential in delivery of kidney-targeted drug and siRNA. With Dr. David Oupicky at UNMC, using recently developed polymeric CXCR4 antagonists, we plan to develop innovative polymer-siRNA conjugates for efficient and safe delivery of siRNA to proximal tubule cells of the injured kidneys.
PROJECT 5: CHARACTERIZATION OF URETERAL OBSTRUCTION IN ROMK DEFICIENT MOUSE: Congenital obstructive nephropathy (CON) remains one of the leading causes of chronic renal failure in children3. In a collaborative project with Dr. Steven Sansom in the department, we will investigate the mechanisms by which ureteral obstruction and its consequence of renal injury develops in ROMK deficient mice.
- Ying Y, Padanilam BJ. Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis? Cell Mol Life Sci. 2016 Jun; 73(11-12):2309-24. PMID: 27048819
- Jang HS, Padanilam BJ. Simultaneous deletion of Bax and Bak is required to prevent apoptosis and interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol. 2015 Sep 15; 309(6):F540-50. PMID: 26180237
- Jinu Kim and Padanilam BJ. Renal denervation prevents long-term sequelae of ischemic renal injury. Kidney Int. 2015 Feb; 87(2):350-8. PMID:25207878
- Kim J, Yoon SP, Toews ML, Imig JD, Hwang SH, Hammock BD, Padanilam BJ. Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy. Am J Physiol Renal Physiol. 2015 Jan 15; 308(2):F131-9. PMID: 25377915
- Ying Y, Kim J, Westphal SN, Long KE, Padanilam BJ. Targeted deletion of p53 in proximal tubule prevents ischemic renal injury in mice. J Am Soc Nephrol. 2014 Dec; 25(12):2707-16. PMID:24854277