Babu Padanilam

Babu PadanilamProfessor
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
Curriculum Vitae

The major focus of the laboratory is to study the mechanisms of cellular injury and renal fibrogenesis in acute kidney injury (AKI) and chronic kidney disease (CKD) models.  The laboratory studies the mechanisms by which selective glycolytic inhibition occurs in the ischemic kidney proximal tubules, which is the primary cause of cellular injury and death. Studies are aimed at understanding 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 in the regulation of renal fibrogenesis in different models.  In addition the laboratory is interested in the mitochondrial regulation of energy homeostasis in animal models of obesity.  Further details of the different projects that are currently underway are presented below.

PROJECT 1:  REGULATION OF GLYCOLYSIS IN ISCHEMIC KIDNEYS: Ischemic renal injury (IRI), generally accepted as the major cause of AKI, results from compromised perfusion of renal tissues. Following IRI, persistent perfusion deficit exists in the outer medullary nephron segments and a metabolic switch from respiration to anaerobic glycolytic energy metabolism ensues as a last resort for ATP synthesis.  However, the glycolytic capacity is inhibited selectively in the medullary proximal straight tubules (PST).  Our studies identified poly (ADP-ribose) Polymerase-1 (PARP-1) and Tp53 inducible glycolysis and apoptosis regulator (TIGAR) to be key molecules that may inhibit glycolysis and initiate the proximal tubular damage.  This project is aimed at understanding the molecular mechanisms by which these two molecules participate in glycolytic inhibition and to determine if intervening in PARP-1 and TIGAR functions may modulate PST injury and the pathogenesis of AKI.

PROJECT 2:  REGULATION OF APOPTOSIS IN ISCHEMIC KIDNEYS:  In patients where AKI is established, the PST undergo necrotic and/or apoptotic cell death or autophagy. However, the exact mechanisms by which renal tubular cells undergo either necrotic or apoptotic form of cell death have not been well defined.  Our studies identified that the p53 target Siva to be a key regulator of apoptosis in this setting.  This project will address the mechanisms by which Siva induces apoptosis in the ischemic kidney.

PROJECT 3: 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 4:  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 5:  MITOCHONDRIAL DYSFUNCTION IN HIGH FAT DIET-INDUCED OBESITY: Our studies show that deficiency in the mitochondrial matrix protein, cyclophilin D (cypD) prevents diet-induced obesity in mice and the data are published in FEBS Letters 2011.  We are currently pursuing this project by generating tissue specific knockout for cypD using cre-loxp technology.  Further we are screening for novel small molecule inhibitors of cypD,  that are candidates for preventing diet-induced obesity and its consequences. 

Acute Kidney Injury

Recent publications:

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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